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Lecture 1 anti viral agents
This document provides information on antiviral drugs, including their mechanisms of action and examples of major drugs used to treat different viral infections. It discusses how antiviral drugs work by blocking viral penetration, inhibiting viral DNA or RNA polymerase, or inhibiting reverse transcriptase. Major antiviral drugs mentioned include acyclovir, ganciclovir, foscarnet for herpes viruses, amantadine and rimantadine for influenza, entecavir and adefovir for hepatitis B, and various nucleoside and nucleotide reverse transcriptase inhibitors as well as protease inhibitors for HIV. The document also reviews the adverse effects and guidelines for use of these various antiviral agents.
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Lecture 1 anti viral agents
- 1. ANTIVIRAL DRUGS Dr. Gyanendra RajJoshi PharmD, RPh 1
- 2. Virus :Obligate parasite Virusparticles (virions) consist of following parts: • Genetic material (DNA or RNA). • Protein coat (capsid) that surrounds nucleic acid. • Envelope (contains lipids and lipoproteins) that surrounds the capsid when virus is outside a cell. 2
- 3. DNA Virus: Pox virus(small pox) Herpes virus Adeno virus ( conjunctivitis , sore throat) Hepadna virus ( HBV) Papilloma virus ( warts ) RNA virus Rubella virus ( German Measles) Rhabdo virus ( rabies) Picorna virus ( polio, meningitis, cold , Hepatitis A) Arena virus (lassa fever) Flavi virus (yellow fever , HCV) Orthomyxo virus (Influenza) Paramyxo virus (mumps , measles) Corona virus (cold , SARS) 3
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- 5. Mechanism of action Majordrugs Block viral penetration/ uncoating Amantadine, enfuvirtide, maraviroc Inhibit viral DNA polymerase Acyclovir , foscarnet, ganciclovir Inhibit RNA polymerase Foscarnet , ribavirin Inhibit viral Reverse transcriptase Zidovudine, didanosine,zalcitabine , lamivudine, stavudine, neprapine , efavirenz Inhibit viral aspartate protease Indinavir, ritonavir, saquinavir , nelfinavir Inhibit viral neuraminidase Zanamivir, oseltamivir 6
- 6. 1. Anti Herpesagents Acyclovir Valacyclovir Famciclovir Ganciclovir Foscarnet Penciclovir Cidofovir Idoxuridine 7
- 7. 3. Anti HBVAgents Adefovir Entacavir 4. Anti-Influenza Virus Amantadine Rimantadine 5. Nonselective Antiviral Drugs Ribavirin Lamivudine Adefovir Interferons 8
- 8. Anti Herpes Drugs Herpesviridaefamily- HSV-1, HSV-2, VZV, CMV Mouth, face skin, esophagus , brain----HSV-1 Genitals , rectum, skin , hands, meninges----HSV-2 Arrest DNA synthesis by inhibiting viral DNA polymerase . Most of them prodrugs Require Viral and Host cellular enzymes ( eg. Thymidine deoxyguanosine kinase ) to phosphorylate them into active triphosphate form Common mechanism of resistance is alteration in viral enzymes 9
- 9. Mechanism of actionof Anti Herpes agents 10
- 10. Acyclovir • Synthetic analogueof guanosine • Valacyclovir is a prodrug Acyclovir monophosphate is phosphorylated to triphosphate , gets incorporated into Viral DNA and inhibits replication. HSV thymidine kinase DNA polymerase Chain termination Suicide inactivation Spectrum: HSV-1, HSV-2, VZV Never totally cure 11
- 11. • Advantage: – Nohematotoxicity, no myelosupression – Treatment of herpes encephalitis • Resistance : – Absence or partial production of TK – Altered TK specificity – Altered viral DNA polymerase • Adverse effects : – – – – – PEG base topical effects Oral- nausea , vomiting , diarrhoea and headache Dose dependent renal impairment , crystallie nephropathy Neurological – lethargy , confusion , tremors Rash , itching and phlebitis at injection site 12
- 12. Ganciclovir • Similar toacyclovir • First phosphorylation viral specific, TK in HSV, Phosphotransferase (UL97) in CMV • Triphosphate form inhibits viral DNA polymerase and causes chain termination • HSV, VZV, CMV reitinitis in HIV patients • Dose limiting hematotoxicity, mucositis , fever, rash , crystalluria • Seizures in overdose 13
- 13. Foscarnet Inorganic pyrophosphate analoginhibitory for herpes and HIV • Not an antimetabolite • Interacts directly with Viral DNA polymerase or HIV reverse transcriptase • Blocks binding site of pyrophosphate and inhibits cleavage • IV 14
- 14. • • • • • • • • • • Nephrotoxicity Hypocalcemia Acute tubular necrosis Crystalluria CNS– tremor, irritabilty, seizure , halluccination, Rash, fever,nausea, vomiting Anemia, LFT,ECG Avoid pentamidine iv CMV retinitis Ganciclovir resistant infections in AIDS 15
- 15. Anti-influenza agents • Amantadine/rimantadine – – – – – – – – – – – – Tricyclic amines Low concentration inhibits replication Rimantadine more active , also for Trypanosoma brucei Inhibit attachment, penetration and viral uncoating M2 protein inhibition Potentiate acid pH induced changes in hemaggluttin during intracellular transfer Minor Dose related GIT and CNS effects Atropine like Livedo reticularis Insomnia Loss of appetite Teratogenic 16
- 16. Oseltamivir/zanamivir – Absorbed rapidlyand cleaved to active carboxylate – Selective inhibitor of vial neuraminidase and leads to viral aggregation and reduced spread – Nausea , abdominal discomfort—given with food – Nasal and throat irritation – Flu like – Influenza A and B 17
- 17. Ribavirin • Monophosphorylated forminhibits IMP dehydrogenase and as a result depletes intracellular nucleotide reserves. • Triphosphate inhibits viral RNA polymerase and end capping of viral RNA • Used as an adjunct to IFN in HCV infection • Management of respiratory syncytial virus • Lassa fever • Hematotoxic • Upper airway irritation • Teratogenic 18
- 18. Anti hepatitis agents •Adefovir dipivoxil – Acyclic phosphonate nucleotide of adenosine monophosphate – Adefovir diphosphate is competitive inhibitor of DNA polymerase and reverse transcriptase – Chain terminator – Chronic HBV – Lamivudine resistant HBV strains – Reduced carnitine – Dose related nephrotoxicity/tubular dysfunction – Headache , abdominal discomfort, diarrhoea , asthenia – Hepatotoxicity ,lymphoid toxicity 19
- 19. Interferons • Potent cytokines •Antiviral, immunomodulating and antiproliferative • Synthesised by host cells • Types – – α, β- all cells, stimulate MHC antigen – γ - T lymphocytes / NK cells • Pegylated interferon • Inhibit protein synthesis , activate endoribonuclease 20
- 20. • Acute influenzalike syndrome – fever , chills, headache, myalgia , arthralgia, nausea , vomiting and diarrhorea • Tolerance • Dose limiting – myleosuppression • Neurotoxicity- confusion • Hepatotoxicity • Condyloma acuminata( genital warts ) • Chronic HCV, HBV • Kaposi Sarcoma in HIV • Multiple sclerosis 21
- 21. Anti HIV Agents/AntiRetroviral Agents i. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Zidovudine (AZT) Didanosine (DDI) Emtricitabine (FTC) Lamivudine (3TC) Zalcitabine (ddC) Abacavir (ABC) ii. Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) Tenofovir Disproxil Fumarate iii. Non-nucleoside reverse Transcriptase Inhibitors ( NNRTIS) Delavirdine Efavirenz Nevirapine Etravirine 22
- 22.
- 23. Reverse Transcriptase Inhibitors •NRTIs : Inactive until phosphorylated by human cellular kinases Used together with protease inhibitors • NNRTIs: – Not prodrugs – No myelosupression – Efavirenz, nevirapine 24
- 24. Side effects ofNRTIs • Zidovudine AZT – hematotoxicity – Headache , myalgia , myopathy , peripheral neuropathy • Didanosine DDI – Pancreatitis – Peripheral neuropathy, hyperuricemia, liver dysfunction 25
- 25. • Zalcitabine DDC –Peripheral neuropathy – GI distress, pancreatitis, neutropenia, rash • Stavudine D4T – Peripheral neuropathy – Myelosupression • Lamivudine 3TC – GI effects and neutropenia 26
- 26. • ADRs ofEfavirenz (a NNRTI) – Not during pregnancy – Dizziness – Vivid dreams 27
- 27. Protease inhibitors • Aspartateprotease (pol gene encoded) cleaves precursor polypeptides to form the proteins of mature virion core • Selective to dipeptide structure of viral proteins • Combined with NRTIs • Indinavir , ritonavir 28
- 28. Adverse effects ofPI • • • • • • Paresthesia Diarrhoea Nausea and vomiting Hypertriglyceridemia Hyperglycemia Hypercholesterolemia 29
- 29. Fusion inhibitors Enfuvirtide : Maraviroc: • Binds gp41 and inhibits fusion of HIV to CD4+ cells • injection site reactions (pain, hardening of skin, erythema, nodules, cysts, itch) • Blocks CCR5 on T cell surface to prevent viral entry • hepatotoxicity allergic reactions (systemic), skin rash, fever, abd. pain, muscle/joint pain, cough, URTI, sleep disturbances 30
- 30. HIV treatment guidelines •99% cell kill • Need of Combination therapy • CD4 cell count (≥350/mm3) 31
- 31. Highly Active AntiRetroviral therapy Combinations : 1) 2 NNRTI+ PI Efavirenz + nevirapine + atazanavir/ritonavir nevirapine + etravirine + lopinavir/ritonavir 2) 2 NRTI+ PI Tenofovir + emtricitabine + ritonavir Abacavir + lamivudine + ritonavir Zidovudine + lamivudine +ritonavir 32
- 32. Combinations to avoid: •Didanosine+Zalcitabine • Stavudine + zidovudine 33
- 33. HIV Postexposure Prophylaxis(PEP) Contact with blood /fluid or blood transfusion Sharp injury or needle stick of HIV infected NRTIs for 28 days/ with triple therapy (dual NRTIs plus a boosted PI) 34
- 34. Prevention of mother-to-childtransmission •Start Zidovudine (AZT) from 28 weeks or as soon as possible thereafter, be provided with single-dose Nevirapine (NVP) when entering labour, and be given AZT+3TC for one week following delivery 35
- 35. Quick Review ofAntiviral Agents • • • • Anti herpetics Anti influenza agents Anti hepatitis viral infections Anti retroviral drugs 36