Anti-viral drugs.pdf

Anti-viral drugs  Virus: introduction Active only when within host cells hence called obligate parasites Uses host cell machinery for metabolism and replication Cannot replicate on its own uses the host cell’s energy to synthesize protein, DNA, and RNA Not only replicate in...

Anti-viral drugs  Virus: introduction Active only when within host cells hence called obligate parasites Uses host cell machinery for metabolism and replication Cannot replicate on its own uses the host cell’s energy to synthesize protein, DNA, and RNA Not only replicate in host cells but direct them to make new viral particles Difficult to find antiviral drug that would selectively attack virus without being toxic to host Contain either DNA or RNA  Introduction Virus is an ultramicroscopic infectious parasites consisting essentially of nucleic acid enclosed in protein coat 9/17/2024 Dr.T.V.Rao MD 4 Classification of viruses Contd….  Stages of viral replication Cell entry – attachment - penetration Uncoating Transcription of viral genome Translation Assembly of virion components Release 9/17/2024 Dr.T.V.Rao MD 7 9/17/2024 Dr.T.V.Rao MD 9 Antiviral drugs: classification Antiretroviral Non Antiretroviral Antiherpes virus Acyclovir, Valacyclovir, Penciclovir, Famciclovir, Cidofovir, Foscarnet, Idoxuridine Anti-influenza virus Amantadine, Oseltamivir, Rimantadine, Zanamivir Anti-hepatitis virus Hepatitis B: Lamivudine, Adefovir, Tenofovir, Entecavir Hepatitis C: Ribavirin, Interferon α Others: Palivizumab, Imiquimod  Anti-Retroviral drugs Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine, didanosine, stavudine, lamivudine, abacavir, emtricitabine, tenofovir Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine, efavirenz, delavirdine Retroviral protease inhibitors (PIs) Ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, amprenavir, lopinavir Entry (fusion) inhibitor: Enfuvirtide CCR5 receptor inhibitor : maraviroc Integrase inhibitor: raltegravir Classification of antiviral drugs on the basis of mechanism Block viral attachment, penetration, uncoating Amantadine, enfuvirtide, maraviroc Inhibit viral DNA polymerase Acyclovir, foscarnet, ganciclovir Inhibit RNA polymerase Foscarnet , ribavirin Inhibit viral reverse transcriptase Zidovudine, lamivudine, didanosine, nevirapine Inhibit viral protease Indinavir, ritonavir, saquinavir, nelfinavir Inhibit viral neuraminidase Oseltamivir, zanamivir Anti-herpes virus drugs Acyclovir, Valacyclovir, ganciclovir, Penciclovir, Famciclovir, Cidofovir, Foscarnet, Idoxuridine MOA (acyclovir) Converted to acyclovir triphosphate inside virus infected cells (by Herpes virus specific enzyme Thymidine kinase and host cell enzyme).  Acyclovir triphosphate inhibits DNA synthesis and replication in 2 ways. I. competitively inhibits viral DNA polymerase  inhibition of viral DNA synthesis and replication. II. gets incorporated into the DNA and cause chain termination. Anti-herpes virus drugs: Spectrum of activity Herpes simplex virus-1 (HSV-1) Herpes simplex virus-2 (HSV2) Varicella-Zoster virus (VZV) Epstein-Barr virus (EBV): weaker Cytomegalovirus (CMV): weaker Uses of anti-herpes virus HSV infections Mucocutaneous and genital herpes prophylaxis of herpes infections in AIDS and immunocompromised patients. H. simplex encephalitis H. simplex keratitis VZV infections Herpes zoster Chickenpox (in immunodeficient and neonates) CMV infections including retinitis (Ganciclovir, cidofovir, foscarnet) Anti-herpes virus: ADR Topical: Stinging and burning sensation after each application. Oral: headache, nausea, malaise Intravenous: Rashes, sweating, emesis and fall in BP occur only in few patients Nephrotoxicity and reversible neurotoxicity (headache, lethargy, altered sensorium, hallucinations, tremor, delirium, seizures etc.) Myelosuppression with gancyclovir Ocular toxicity and Carcinogenicity with cidofovir  Note Acyclovir has very short t1/2,requires multiple dosing. Primarily excreted by kidney. It is essential to maintain hydration while the patient is on acyclovir therapy because dehydration increases its nephrotoxic potential. Valacyclovir has a long t1/2 and gets converted to acyclovir by hepatic metabolism. Ganciclovir is used only I.V. whereas valganciclovir has good oral absorption. Valacyclovir is the DOC in herpes zoster as its bioavailability is 4-5 times more of orally administered acyclovir. Anti-influenza agents Influenza virus A, B, C Influenza A: Seasonal flu H3N2 Avian flu(bird flu) H5N1 Swine flu H1N1 Agents: Oseltamivir and zanamavir Amantadine and rimantadine  Anti-influenza agents: Oseltamivir, zanamivir Inhibit the release of virions from infected host cell by inhibiting the enzyme neuraminidase. [Neuraminidase cleaves sialic acid group from glycoprotein of host cell to cause release of virions] Oseltamivir used orally Zanamivir via inhalation directly to the respiratory tract Use: Prophylaxis and treatment of influenza A and B Oseltamivir is DOC for bird flu (H5N1) and swineflu (H1N1). ADR: Oseltamivir: Headache, fatigue, nausea, vomiting Zanamivir: Cough, bronchospasm Anti-influenza agents: amantadine, rimantadine Mechanism of action Blocks attachment, penetration and uncoating of Influenza-A virus within host cells thus preventing replication Uses: Prophylaxis and treatment of influenza A Also in parkinsonism ADR GI upset Neurotoxicity: nervousness, insomnia, seizure Antihepatitis agents Drugs active against hepatitis B (HBV) and hepatitis C (HCV) are Lamivudine, Tenofovir, emtricitabine, Interferon α, Entecavir and Adefovir. Goal of therapy in chronic HBV is to sustain suppression of HBV replication whereas in HCV, it is viral eradication. Antihepatitis agents Anti HBV agents Viral DNA polymerase inhibitor: Entecavir and Adefovir. Nucleoside reverse transcriptase inhibitors (NRTIs): Lamivudine, Tenofovir, emtricitabine Interferon α ADR GI disturbances; CNS toxicity musculoskeletal and dermatological effects blood disorders metabolic effects including pancreatitis, liver damage, lactic acidosis and lipodystrophy Adefovir Is effective against hepatitis B virus. Available as adefovir dipivoxil which is a prodrug of adefovir and is rapidly converted to adefovir by the esterases in the blood and intestines. Adefovir is phosphorylated by viral kinase to adefovir diphosphate which inhibits viral DNA polymerase. This enzyme is inhibited and adefovir itself gets incorporated in the viral DNA resulting in termination of DNA chain. Cont… Can cause headache, diarrhoea, weakness and abdominal pain. Nephrotoxicity and lactic acidosis has been reported. Adefovir is used orally in the treatment of chronic HBV infection and is particularly useful in lamivudine resistant HBV patients. Entecavir Guanosine nucleoside analog that inhibits DNA polymerase. It is completely absorbed on oral administration, but should be given on an empty stomach. It is well tolerated. Entecavir is first line drug for chronic HBV infection. Antihepatitis agents: Antihepatitis C Ribavirin, Interferon α Ribavirin: broad spectrum antiviral activity(DNA as well as RNA virus) MOA: Inhibits viral RNA synthesis Uses: DOC for HCV(both acute & chronic) with Peg-IFN-α Used in influenza A and B, RSV (Respiratory syncytial virus) ADR: Anaemia, bone marrow depression, hemolysis, neurotoxicity, teratogenicity. Antihepatitis agents: Interferon α Immunomodulator Acts on JAK-STAT binding receptor  increased production of antiviral proteins and natural killer cells Interferons are natural proteins produced by the cells of the immune systems in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. Antiviral, immune modulating and anti-proliferative action.  Three classes of interferons – α , β, γ γ has less anti-viral activity compared to α and β interferons ADR: Fever, GI upset Flu-like symptoms, anorexia and fatigue Neurotoxicity Myelosuppression 9/17/2024 Dr.T.V.Rao MD 30  Treatment of viral hepatitis Acute hepatitis: HBV: Symptomatic therapy , no antiviral drug required HCV: Peg-interferon-α-2b + Ribavirin Chronic hepatitis: HBV: Entecavir (DOC) Alternatives: Oral: Lamivudine, Adefovir, Tenofovir Subcutaneous: Interferon-α-2b, Peg-interferon-α-2a HCV: Peg-interferon-α + Ribavirin Topical antivirals Antiherpes virus Acyclovir Penciclovir Idoxuridine Trifluridine Imiquimod Imiquimod Is a topical antiviral agent used in the treatment of external genital and perianal warts due to human HPV. MOA Induces cytokine release reduction in viral load and wart size ADR of Imiquimod Erythema Itching or burning sensation Edema Erosions, ulcerations rare Flu like symptoms Antiretroviral agents  HIV AIDS: an overview AIDS first characterized in 1980s; 1st case reported in USA Most HIV infections – Due to HIV-1 Continued decline of CD4+ - T lymphocyte Opportunistic infections & malignancies appear Risk factors : Sexual contact Parenteral exposure Perinatal exposure 1987 – 1st drug Zidovudine approved by FDA  HIV AIDS: an overview Acquired immunodeficiency syndrome[AIDS] results from infection with Human immuno-deficiency virus[HIV]- a single stranded RNA retrovirus. That forms its DNA from RNA with the help of the enzyme RNA dependent DNA polymerase (reverse transcriptase). Two types of HIV have been identified-HIV-1 and HIV-2. Anti-retro viral drugs are useful in prolonging and improving the quality of life and postponing complications, but do not cure the infection The primary cell type attacked by HIV is the CD4+ helper T-lymphocyte Basic component of HIV  Anti-Retroviral drugs: classification Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine, didanosine, stavudine, lamivudine, abacavir, emtricitabine Nucleotide reverse transcriptase inhibitors (NtRTIs): tenofovir Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Nevirapine, efavirenz, delavirdine Retroviral protease inhibitors (PIs) Ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, amprenavir, lopinavir Entry (fusion) inhibitor: Enfuvirtide CCR5 receptor inhibitor: maraviroc Integrase inhibitor: raltegravir  HIV enters the CD4 cells after fusion of viral GP41 with CCR5 or CXCR4 receptors on human cells. After entry, viral RNA is converted to DNA with the help of reverse transcriptase (RNA dependent DNA polymerase). This viral DNA integrates with human DNA to form provirus with the help of enzyme, integrase.. This proviral DNA can replicate and transcript to form RNA which forms proteins via translation. The proteins formed initially are inactive and require protease enzyme for activation. Complete virus is generated from these components, which leaves CD4 cells to infect other cells. Various drugs can target these steps. Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine, didanosine, stavudine, lamivudine, abacavir, emtricitabine Effective for both HIV I and II. MOA: Prodrugs  activated by host cell kinases to form triphosphates. competitively inhibit HIV reverse transcriptase  and also act as chain terminators by incorporation into the DNA chain  NRTIs: ADR Bone marrow suppression mostly with Zidovudine Anemia, neutropenia, thrombocytopenia Peripheral neuropathy, Lipodystrophy syndrome & lactic acidosis mostly with stavudine Pancreatitis, Hyperuricemia, optic neuritis, fulminant hepatic failure mostly with didanosine Myopathy, Nail hyperpigmentation with Zidovudine. Nephrotoxicity except abacavir Zidovudine and stavudine should not be combined Compete for intracellular phosphorylation  pharmacological antagonism All NRTIs may cause lactic acidosis, hepatomegaly and steatosis. Note: Lamivudine and emtricitabine are best tolerated NRTIs. Individual agents Zidovudine : Backbone of combination therapy Analogue of thymidine Also used as prophylaxis for post exposure prophylaxis for health workers In vertical transmission ADR :Common + headache, nausea, vomiting, fatigue, myopathy & bone marrow toxicity Contraindications : Anemia, neutropenia, Renal impairment Concurrent use of myelosuppressants  Stavudine Thymidine analogue Competitive inhibitor of HIV -1 RT Use : In HIV as a part of combination therapy; as post exposure prophylaxis Major ADR- peripheral neuropathy Less common ADR – pancreatitis, arthralgias and elevation in serum transaminases.  Lamivudine Nucleoside analogue with active against HIV-1, HIV-2 and hepatitis-B virus. Inhibits RT and synergistic with zidovudine against HIV -1 Best tolerated & less toxic Lamivudine, administered in combination with zidovudine or another nucleoside analogue is indicated for treatment of advanced HIV disease: combination strongly enhances CD4 counts. Also used for post exposure prophylaxis. ADR- Peripheral neuropathy  Nucleotide reverse transcriptase inhibitors (NtRTI) Tenofovir Does not require bioactivation by kinases as it is a nucleotide Also useful in HBV ADR: Rash, fever, nausea, pruritus, Neurotoxicity: Headache, confusion, insomnia, amnesia.  Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Efavirenz, nevirapine, delavirdine, etravirine MOA: non-compititive inhibitors These drugs inhibit reverse transcriptase by acting at a site (allosteric site) different from that of NRTIs. These are selective for HIV-1 and have no activity against HIV-2. ADR: Hypersensitivity: Skin rash Steven Johnson syndrome, toxic epidermal necrolysis mostly with nevirapine Hepatotoxixity with nevirapine Neurotoxicity (insomnia, delusion, mania) mostly with efavirenz Protease inhibitors (PIs) Ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, amprenavir, lopinavir MOA: Competitively inhibit the HIV protease enzyme. Protease enzyme helps in the maturation of infectious virions Inhibit the viral protease enzyme and prevent te cleavage of proteins necessary for virion production, results in immature, noninfectious virions. Cross resistance among PIs, no cross-resistance with reverse transcriptase inhibitors.  Protease inhibitors: ADR Nephrotoxicity: crystalluria and kidney stones. To prevent renal damage, good hydration must be maintained. Hepatotoxicity: asymptomatic Hyperbilirubinemia. Metabolic abnormalities Diabetes mellitus, hyperlipidemia, altered fat distribution (collectively called lipodystrophy syndrome) Except atazanavir ECG abnormalities with atazanavir Drug Interactions All PIs are competitive inhibitors of drugs metabolizes by CYP3A4 family. Hence, life-threatening toxicities (due to increased plasma levels) may result with concurrent use of following drugs. Common drug interactions – Due to ↓ CYP isoform – ↑ level of Cisapride, Triazolam, Midazolam, Statins Phenytoin, Phenobarb., Carbamazepine, Rifampicin- ↓ their efficacy: enzyme inducers may decrease the plasma levels of PIs. Popular Drug Combination Indinavir+Zidovudine+Lamivudine Nelfinavir+Zidovudine+Didanosine Saquinavir+Zidovudine+Zalcitabine Ritonavir+Lopinavir+Stavudine+Lamivudine Ritonavir+Indinavir+Stavudine+Didanosine  Other drugs Entry or fusion inhibitors Enfuvirtide Binds to Gp 41 subunit of HIV envelope protein  inhibition of the fusion of viral and host cell membranes by preventing the entry of HIV-1 into CD4 cells  prevention of entry of the virus in the host cells. It is used subcutaneously and can cause injection site reactions, hypersensitivity and pneumonia. It is used along with other antiretroviral drugs for the treatment of advanced HIV-1 infections( in patients with extensive viral resistance). It is not effective against HIV-2 Maraviroc CCR5 receptor antagonist (one of the two coreceptors) present on CD4 cell membrane and prevents the entry of the virus into the host cell. It prevents interaction of viral gpl20 with CCR-5 coreceptor. It is used along with other antiretroviral drugs in highly treatment-resistant adult patients infected with HIV that binds to CCR-5 receptor. ADR: hepatotoxicity, cough, rash, fever, git distress and joint pain. Integrase Inhibitors Raltegravir : It inhibit the viral enzyme integrase, thereby preventing the insertion of HIV genetic material (DNA) into the chromosomes of the host cells and halting the viral replication process. It is used along with other antiretroviral drugs only in the treatment –resistant adult patients. ADR: nausea, diarrhoea, fever, headache and myopathy. Highly active antiretroviral therapy (HAART) Combination therapy with maximally potent agents will produce complete suppression of viral replication and decrease the likelihood of emergence of resistance. 2 NRTIs + 1 NNRTI/ PI E.g. : Zidovudine+ lamivudine+ nevirapine Zidovudine + lamivudine+ efavirenz Zidovudine + lamivudine+ atazanavir  First-line antiretroviral regimens Preferred regimen: Zidovudine+ lamivudine+ nevirapine(2NRTI+1NNRTI) Alternative regimen: Zidovudine+ lamivudine+ efavirenz(2NRTI+1NNRTI) lamivudine+ Stavudine+ efavirenz(2NRTI+1NNRTI) lamivudine+ Stavudine+ nevirapine(2NRTI+1NNRTI) Other option: lamivudine+ Tenofovir+ nevirapine lamivudine+ Tenofovir+ efavirenz lamivudine+ Tenofovir+ zidovudine Prophylaxis of HIV infection Post exposure prophylaxis Prophylaxis after sexual exposure Perinatal HIV prophylaxis Prevention of vertical transmission to the offspring during pregnancy Post exposure prophylaxis To the victims (Doctors, nurses, paramedics etc) of accidental exposure to HIV infection through surgical instruments, blood transfusion or needle- prick injury Basic regimen Zidovudine 300 mg + Lamivudine 150 mg, each twice a day for 4 weeks Expanded regimen Zidovudine 300 mg + Lamivudine 150 mg, each twice a day + indinavir 800 mg thrice a day for 4 weeks Perinatal HIV prophylaxis Prevention of vertical transmission to the offspring during pregnancy: All HIV positive women, who are not on ART, should be put on the standard 3 drug ART. This should be continued through delivery and into postnatal period. Zidovudine+Lamivudine+Nevirapine OR Zidovudine started during 2nd trimester and continued through the delivery to postnatal period, with treatment of the neonates for 6 weeks. Nasal dosage forms: 1- Nasal Drops and Sprays: Drugs in solution may be instilled into the nose from a dropper or from a plastic squeeze bottle. The drug may have a local effect, e.g. antihistamine, decongestant. Alternatively the drug may be absorbed through the nasal mucosa to exert a systemic effect. The use of oily nasal drops should be avoided because of possible damage to the cilia of the nasal mucosa.