Antiviral Agents
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This document outlines a lecture on antiviral drugs for various viral infections. It begins with learning objectives about classifying antiviral drugs and their mechanisms and clinical applications. It then covers drugs for anti-herpes therapy like acyclovir and valacyclovir; anti-HIV drugs like NRTIs, NNRTIs, and protease inhibitors; drugs for hepatitis B and C like lamivudine, entecavir, and interferon; and drugs for influenza like oseltamivir and zanamivir. The document discusses the mechanisms, uses, dosing, and adverse effects of these various antiviral agents.
Antiviral Agents
- 1. Dr Htet Htet MBBS, MMedSc Lecturer Faculty of Medicine 18th July, 2015 All rights reserved
- 2. • At the end of the lecture, students must be able to – To classify major drug groups and specific examples of drugs for the viral infections (Herpes, HIV, HBV, HCV and influenza). – To describe the mechanism of action of antiviral drugs including their pharmacological actions, important pharmacokinetic parameters, interactions and dosing. – To outline the application of these drugs clinically (eg. Antiretroviral therapy – ART)
- 3. 1. Introduction to viral replication (recall) 2. Drugs used for anti-herpes therapy 3. Drugs used for anti-HIV therapy 4. Drugs used for hepatitis B and C infection 5. Drugs used for influenza
- 4. Introduction • Viruses are obligate intracellular microorganisms, drugs that target viral processes must penetrate host cells. • Therefore, drugs that negatively impact on a virus are also likely to negatively impact normal pathways of the host.
- 5. Steps of viral replication 1. Attachment of the virus to receptors on the host cell surface; 2. Entry of the virus through the host cell membrane; 3. Uncoating of viral nucleic acid; 4. Synthesis of early regulatory proteins, eg, nucleic acid polymerases; 5. Synthesis of new viral RNA or DNA; 6. Synthesis of late, structural proteins; 7. Assembly (maturation) of viral particles; and 8. Release from the cell. Antiviral agents can potentially target any of these steps.
- 7. 1. Introduction to viral replication (recall) 2. Drugs used for anti-herpes therapy 3. Drugs used for anti-HIV therapy 4. Drugs used for hepatitis B and C infection 5. Drugs used for influenza
- 9. Drugs used as anti-herpes agent • Acyclovir • Valacyclovir • Famciclovir • Penciclovir • Docosanol • Trifluridine
- 10. Acyclovir • MOA – Activation – Inhibition of viral DNA synthesis • Activation • Acyclovir requires three phosphorylation steps for activation. • It is converted first to the monophosphate derivative by the virus specific thymidine kinase and then to the di- and triphosphate compounds by host cell enzymes.
- 11. • Inhibition of viral DNA synthesis • Two mechanisms: – competition with deoxy GTP for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex; and chain termination following incorporation into the viral DNA.
- 12. • Selective toxicity • Because it requires the viral kinase for initial phosphorylation, acyclovir is selectively activated—and the active metabolite accumulates only in infected cells. • Pharmacokinetics • Bioavailability – low 15-20% • T ½ - 2.5 – 3hrs • Clearance – via glomerular filtration & tubular secretion • 20 hrs in patient with anuria (anuria - Anuria means nonpassage of urine, in practice is defined as passage of less than 50 milliliters of urine in a day.) • Route – topical, oral and IV
- 13. Therapeutic uses • Oral – genital herpes (recurrent, first episode), herpes labialis, cutaneous zoster, ( decreases the total number of lesions, duration of symptoms and viral shedding) also reduces the post-herpetic neuralgia. • Porphylactically – organ transplant patients to prevent HSV reactivation. • IV – HSV encephalitis (doc), neonatal HSV, serious HSV or VZV • Topical – less effective than oral for primary HSV infection, not benefit for recurrent genital HSV
- 15. Adverse effects • Well tolerated, nausea, diarrhoea may occur • IVI – reversible renal toxicity (crystalline nephropathy) • Can have neurologic effects (need adequate hydration and avoid rapid infusion) • Concurrent use of nephrotoxic agents – enhance potential of nephrotoxicity.
- 16. Drug resistance
- 17. Anti-herpes agents Route of administration Use Dose Famciclovir Oral • Genital herpes (first/recurrent) • Orolabial herpes (first/recurrent) • Herpes zoster Different doses/duration and frequency Valaciclovir Oral Foscarnet IV Acyclovir resistant HSV and VZV infection Ganciclovir Topical Keratitis Every 3 hr while awake Docosanol Topical Recurrent herpes labialis Every 2 hr while awake Penciclovir Topical Herpes labialis or herpes genitalis Every 2 hr while awake Trifluridine Topical Acyclovir resistant HSV infection 5 times a day
- 21. Classification of anti-retroviral agents • 1st agent – zidovudine (1987) • “6” Classes of Anti-retroviral drugs nowadays 1. NRTI (nucleoside/nucleotide Reverse transcriptase inhibitors) 2. NNRTI (non-nucleoside Reverse transcriptase inhibitors) 3. PI (Protease inhibitors) 4. FI (Fusion inhibitors) 5. CCR5 co-receptor antagonists 6. II (HIV integrase strand transfer inhibitors)
- 22. NRTI (nucleoside/nucleotide Reverse transcriptive inhibitors) • Zidovudine (AZT) • Lamivudine (3CT) • Stavudine (d4T) • Didanosine (ddI) • Abacavir • Emtricitabine (FTC) • Tenofovir
- 23. • Mechanism of action – NRTIs act by competitive inhibition of HIV-1 reverse transcriptase – Incorporation into growing viral DNA chain causes premature chain termination due to inhibition of binding with the incoming nucleotide • Status of NRTIs – Considered as “backbone” of the antiretroviral therapy – Used with other agents (NNRTI, PI, or II) – NRTI itself given in pairs but certain combinations should be avoided due to drug interactions, similar resistance patterns or overlapping toxicities
- 24. Adverse effects Comments Zidov- udine AZT Myelosuppression (most common) Macrocytic anaemia or neutropenia • Avoid concurrent stavudine • Avoid other myelosuppressive drugs AZT reduce the phosphorylation of stavudine. Lamiv- udine (3TC) Headache, dizziness, GI side effects Mild and infrequent • Also has activity against HBV*** • One of the recommended ARTs in pregnant women. *** Stavu- dine Dose-related peripheral sensory neuropathy Pancreatitis, arthralgia, aminotransferases, Hepatic steatosis, lactic acidosis • Avoid concurrent administration of neurotoxic drugs • Avoid with ddI (lactic acidosis and pancreatitis) • Avoid with AZT Didan osine Dose-dependent pancreatitis Peripheral distal sensory neuropathy Avoid with stavudine Avoid other neurotoxic
- 25. Adverse effects Comments Emtricitabine(FTC) • Also has activity against HBV*** Tenofovir • Also has activity against HBV***
- 26. NNRTI (non-nucleoside reverse transcriptase inhibitors) • Delavirdine • Efavirenz • Etravirine • Nevirapine • Rilpivirine
- 27. • Mechanism of action – Bind directly to HIV-1 reverse transcriptase, resulting in inhibition of RNA and DNA dependent polymerase activity. – The binding site of NNRTI is near but distinct from that of NRTI. • Status of NRTIs – Unlike NRTI, NNRTIs do not compete with nucleoside or do not require phosphorylation to be active.
- 28. • Adverse effects in general – GI intolerance – Skin rash ( infrequently – Steven-Johnson syndrome) – NNRTIs – either enzyme inducer/inhibitor (potential drug drug interactions) (one of the limitation factors)
- 29. Drug name Therapeutic usefullness Adverse effect Nevirapine used for prevention of mother to child transmission (PMCT) 200 mg single dose at the onset of labor fb 2mg/kg to neonate within 3 days of delivery No evidence of human teratogenicity Maculopapular rash SJ$ Enzyme inducer Delavirdine Skin rash (rarely SJ$) Enzyme inhibitor Should be avoided in preg: Efaviranz Skin rash (rarely life threatening) Both inducer and inhibitor Should be avoided in preg: Etravirine Skin rash (rarely life threatening) Both inducer and inhibitor
- 30. Protease inhibitors • Atazanavir • Darunavir • Fosamprenavir • Indinavir • Lopinavir • Nelfinavir • Ritonavir • Saquinavir • Tipranavir
- 31. Mechanism of action Function of HIV protease enzyme • During the later stage of HIV growth cycle, the gene products are translated into proteins, which become immature budding particles. • HIV protease is responsible for cleaving these precursor molecules to produce the final structural proteins of mature virion core. Activity of PI • PIs prevent the processing of viral proteins into functional conformations, resulting immature, noninfectious viral particles.
- 32. Adverse effects • Redistribution of accumulation of body fat (resulting central obesity, buffalo hump, Cushingnoid appearance.) • Drug drug interactions (extensively metabolized by liver, some are inhibitors and some are inducers). • PI agents when given in combination, acting as pharmacokinetic enhancer rather than antiretroviral agent. • (Ritonavir boosted prolong drug half life.)
- 33. Enfuvirtide (Fusion inhibitor) Mechanism of action Enfuvirtide • Fusion inhibitor that blocks HIV entry into the cell. • Binds to GP41 subunit of the viral envelope glycoprotein preventing the conformational change required for the fusion of viral and cellular membranes. • Must be administered SC. • Adverse effect: - local injection site reactions.
- 35. Mechanism of action Maraviroc • Binds to host protein CCR5, one of the two chemokine receptors necessary for entrance of HIV into CD4+ cells. • Is active against HIV that uses the CCR5 co-receptor exclusively, not against HIV strains with CXCR4. • CI in patients with severe or end stage Renal impairment. Maraviroc (entry inhibitor)
- 37. Integrase inhibitors • Dolutegravir • Elvitegravir • Raltegravir Mechanism of action • INSTIs bind integrase, a viral enzyme essential to the replication of both HIV-1 and HIV-2. • It inhibits strand transfer. • And interfering the integration of reverse-transcribed HIV DNA into the chromosomes of the host cells.
- 39. • The accepted standard for HIV treatment is that combination “highly active anti-retroviraltherapy (HAART)” should be administered before substantial immunodeficiency intervenes. • The primary aim of treating patients with HIV infection is – maximal suppression of HIV replication for as long as possible. To decrease viral load – To improve survival.
- 40. Malaysian guideline for HIV
- 42. • during pregnancy initiated at 14-34 weeks up to onset of labour – oral AZT 600 mg/day in divided dose • during labour IV. AZT 2mg/kg in 1 hr followed by 1 mg/kg/hr till delivery • infant AZT 2mg/kg 6 hrly up to 6 weeks • Nevirapine 200 mg single oral dose at onset of labour and 2mg/kg single oral dose at 48-72 hrs after delivery (47% ↓)
- 43. • Individuals are eligible for HIV PEP if – – The exposure occurred within the past 72 hours and – The exposed individual is not infected with HIV and – Non-intact skin or mucous membrane was significantly exposed to a potentially infectious body fluid – And the source is HIV infective or the HIV status is unknown. • PEP treatment with 2 NRTIs – – A regimen with 2 NRTIs is recommended if • HIV status of the source person is unknown and • The background prevalence of resistance to ART is <15% and • the source person has never used ART or • the source person is unlikely to have ART resistance based on ART therapy. • Recommended two-drug combination therapy for HIV PEP ( given for 28 days) – AZT + 3 TC – Alternative is TDF + 3TC – NVP and ddI are not used due to their relatively higher risk of potentially serious side effects.
- 45. What is boosted regimen? • Pharmacologic enhancer • Ritonavir is the ideal • It inhibits two key stages of metabolism – First pass metabolism – Inhibit CYP3A4 in the hepatic metabolism • Result – Less drug is transported back out of the cell, thereby increasing the drug’s half life.
- 47. The goals of chronic HBV therapy • To sustain suppression of HBV replication, resulting in slowing of progression of hepatic disease(with retardation of hepatic fibrosis and even reversal of cirrhosis), • To prevent complications (ie, cirrhosis, hepatic failure, and hepatocellular carcinoma), and • To reduce the need for liver transplantation.
- 48. • Suppression of HBV DNA to undetectable levels, • Seroconversion of HBeAg (or more rarely, HBsAg) from positive to negative, and • Reduction in elevated hepatic transaminase levels. How does it carry out?
- 49. Indication in chronic hepatitis B Route of administration NNRTI ADEFOVIR + Oral ENTECAVIR + Oral LAMIVUDINE + Oral TENOFOVIR + Oral TELBIVUDINE + Oral INTERFERON INTERFERON-ALPHA-2b + SC or IM PERGYLATED INTERFERON- ALPHA-2a + SC Drugs used for HBV infection, 7 drugs (2013)
- 50. What is pergylated interferon? • Use of polyethylene glycol-complexed interferon alfa-2a and alfa-2b • Results in – Slower clearance – Longer terminal half-lives – Steadier plasma drug concentrations – Allowing for less frequesnt dosing
- 51. Pharmacology of interferon • What is interferon? Interferons are host cytokines that exert complex antiviral, immunomodulatory and antiproliferative actions and some has proven to be useful for both HBV and HCV.
- 52. Pharmacology of interferon • MOA – Interferons appear to functions by Induce intracellular signals following binding to specific cell membrane receptors, resulting inhibition of viral penetration, translation, transcription, protein processing, maturation and release as well as increased host expression of MHC, enhanced phagocytic activity of macrophages, augmentation of the proliferation and survival of cytotoxic T cells.
- 53. • Adverse effects – Ful like syndrome within 6hrs of dosing. – Transient hepatic enzyme elevations – Neurotoxicities • CI – Hepatic decompensation – Autoimmune disease – History of cardiac arrhythmia
- 54. Hepatitic C
- 55. • Primary goal of therapy – Viral eradication • Drugs used for treatment of hepatitis C infection – Polymerase inhibitors (sofosbuvir) – Protease inhibitors (boceprevir, simeprevir, telaprevir) – Ribavirin
- 57. MOA Polymerase inhibitors (sofosbuvir) inhibits the HCV RNA dependent DNA polymerase. Protease inhibitors (Boceprevir Simeprevir Telaprevir) Inhibit HCV replication directly by binding to the protease that cleaves the HCV encoded polyproteins. Ribavirin Inhibit viral messanger RNA. Inhibit viral RNA dependent DNA polymerase. Inhibit replication of a wide range of RNA and DNA viruses – influenza A, B, parainfluenza, respiratory syncytial virus, paramyxoviruses, HCV and HIV-1.
- 59. Oseltamivir & Zanamivir Amantidine & rimantidine MOA • Neuriminidase inhibitors • Interfere with release of progeny influenza virus from infected host cells • Halting the spread of infection within the respiratory tract • blocks M2 proton ion channel of the virus particle and inhibit the uncoating of viral RNA within infected host cells plus preventing its replication. Route of administration O – oral Z – inh Oral Activity Active against Influenza A and B Only against influenza A Dosing and benefits • Early administration is crucial because replication of influenza virus peaks at 24-72 hours after the onset of illness. • Initiation of 5 day course of therapy within 48 hours after the onset of illness decreases the duration of symptoms, viral shedding and transmission, and rate of complications such as pneumonia, asthma, hospitalization and mortality. • When begun within 1-2 days after the onset of illness, the duration of fever and systemic symptoms is reduced by 1-2 days.
- 62. References • http://www.moh.gov.my/images/gallery/Garispanduan/HIVGUID ELINES.pdf • http://www.who.int/hiv/pub/guidelines/arv2013/download/en/( accessed18th July, 2015) • http://www.moh.gov.my/images/gallery/Garispanduan/HIVGUID ELINES.pdf • Sharon Safrin . (2015). Antiviral agents . In: Katzung, BG, Trevor, AJBasic and Clinical Pharmacology . 13th ed. USA: McGraw-Hill . p835-863.