Preliminary_20231218_Antiviral Drugs.pdf

Pharmacology Iva D. Tzvetanova, Ph.D. Office Hours: Currently by appointment Email: [email protected] Link to Office Hours Booking: https://outlook.office365.com/owa/calendar/[email protected]/bookings/ Antiviral and Antiretroviral Drugs Goal - target an essential viral en...

Pharmacology Iva D. Tzvetanova, Ph.D. Office Hours: Currently by appointment Email: [email protected] Link to Office Hours Booking: https://outlook.office365.com/owa/calendar/[email protected]/bookings/ Antiviral and Antiretroviral Drugs Goal - target an essential viral enzyme or protein to inhibit a pathway unique to the virus but not the cell Virus Facts  Obligate intracellular parasites  Have no energy-generating enzymes  Require the metabolic processes and activities of the host cell ➔In order to reproduce a virus needs to:  Infect a cell ➔ enter  Use the host machinery to synthesize the macromolecules necessary for assembly of new viral particles ➔ Obligate intracellular parasites Viruses contain:  DNA or RNA - not both  Capsule  Envelope – SOME but not all Are viruses susceptible to antibacterial agents? NO Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy Stages of the Viral Life Cycle Attachment to host cell  Specific ligands (antireceptors) on the virus bind to specific receptors on the host cell surface Entry  Endocytosis or  Direct fusion with host cell membrane (e.g. HIV and measles) or  Receptor-mediated endocytosis (e.g. influenza, Epstein—Barr and …) Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy Simplified View of the Transmission and Life Cycle of SARS-CoV-2 Causing COVID-19 Funk et al. Fronteers in Pharmacology 2020 Stages of the Viral Life Cycle Viral Uncoating i.e. release of viral nucleic acid (RNA or DNA) from the capsid Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy Stages of the Viral Life Cycle Inside the host - Expression of viral genome and synthesis of new viruses Host cell machinery is crucial here 1. Transcription - if DNA virus 2. Translation ➔ viral proteins are synthesized - these are key for new viral synthesis 3. Replication of viral genome 4. Assembly and maturation of daughter viruses ➔ virus spreads in host cell 5. Release of daughter viruses from the host cell ➔ virus can spread in host and find new hosts Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy What are the major challenges in treating viral infections?  Clinical symptoms appear late – the virus has already replicated ➔Inhibitors of viral entry and replication – of very limited effectiveness at this stage Overview - Mechanisms of Action of Antiviral Agents Cytotoxic T lymphocytes (specific immune response)  Recognize proteins on viral surface ➔ destroy viruses Antibodies can INactivate viruses Interferons  Released by virus-infected cells  Stimulate production of antiviral proteins in neighboring cells ➔ Destroy or suppress viral genome ➔ Prevent viral protein synthesis Simmons Pharmacology: An Illustrated Review Inhibitors of Nucleic Acid Synthesis e.g. Acyclovir, ganciclovir  Most are nucleoside analogues  Act as false nucleosides ➔ Incorporated into viral DNA - BUT are the WRONG building blocks ➔ Terminate chain elongation ➔ Inhibit viral replication  MUST BE phosphorylated intracellularly to exert their antiviral effects – i.e. prodrugs Chemical Structure of Virustatic Antimetabolites Simmons Pharmacology: An Illustrated Review Antiherpes FIX Anti-HIV Anti-hepatatis Anti-RNA viruses Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy Activation of Acyclovir and Inhibition of Viral DNA Synthesis 3′-OH group of deoxyribose is required for the attachment of additional nucleotides Simmons Pharmacology: An Illustrated Review Inhibitors of Nucleic Acid Synthesis Acyclovir, Cidofovir, Famciclovir, Penciclovir Selective toxicity – remarkable  Target virus-specific  Thymidine kinase + Viral DNA polymerase Spectrum  Herpes simplex virus (HSV)  Varicella zoster virus i.e. herpes zoster (shingles) Pharmacokinetics  Acyclovir – low oral bioavailablity - accumulates in patients with renal failure  The rest – good oral bioavailablity - longer t1/2 ➔ lower frequency of dosing Resistance – due to mutations in viral thymidine kinase and DNA polymerase Could not fit here – but nice figure in your book Ganciclovir and Valganciclovir Ganciclovir and Valganciclovir  100X more active against cytomegalovirus (CMV) infections than is acyclovir ➔ use should be limited to treating CMV infections in immunocompromised patients Inhibitors on Nucleic Acid Synthesis And Neutropenia ➔Reserved for use in CMV infections that are resistant to other drugs Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Antiherpes FIX Anti-HIV Anti-hepatatis Anti-RNA viruses Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy Inhibitors of Nucleic Acid Synthesis What about RNA viruses? Other Select Inhibitors of Nucleic Acid Synthesis Ribavirin - Phosphorylated to mono-, di-, and triphosphate forms - Interferes with viral RNA polymerases - Effective against respiratory syncytial virus (RSV) and hepatitis C - Administered as an aerosol to limit systemic toxicity (hemolytic anemia) (but oral for HepC) Ribavirin is a teratogen Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Other Select Inhibitors of Nucleic Acid Synthesis Pyrophosphate analogue Foscarnet activation in the host ➔ does NOT require - Inhibits viral DNA and RNA polymerases BUT Renal toxicity, hypokalemia (seizures and arrhythmias) ➔ reserved for use in CMV infections resistant to other drugs or in patients with HIV Which drugs covered so far are prodrugs? Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Viral M2 Protein Blockers e.g. Amantadine & Rimantadine Specifically prevent viral uncoating by blocking a viral ion channel (= viral M2 protein) Prophylaxis for Viral Flu (Influenza A and Amantadine) Influenza A is endocytosed into cells BUT proton from endosome is needed for uncoating + release of viral RNA Amantadine blocks viral channel ➔ Specifically prevents proton influx ➔ Specifically prevents uncoating Simmons Pharmacology: An Illustrated Review FIX Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy Amantadine & Rimantadine Pharmacokinetics Absorption – Oral – complete  Excretion - Can be excreted unchanged in the urine Used for - prophylaxis and treatment of influenza A virus infections Side effects - central nervous system side effects (esp. amantadine) - nervousness - confusion - insomnia - light-headedness - hallucinations CNS side effects are the most common Why? Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Prophylaxis for Viral Flu (Influenza A and Amantadine) Influenza A is endocytosed into cells BUT proton from endosome is needed for uncoating + release of viral RNA Amantadine blocks viral channel ➔ Specifically prevents proton influx ➔ Specifically prevents uncoating Simmons Pharmacology: An Illustrated Review Selective Neuraminidase Inhibitors for Influenza A and B e.g. Oseltamivir and Zanamivir  Influenza A and B have viral neuraminase  Viral neuraminase – splits off N-acetylneuraminic (sialic) acid residues on the cell surface coat ➔ Newly formed virus particles can be detached from the host cell Without active neuraminidase  Hemagglutinin of the virus binds to sialic acid ➔ clumps ➔ virus cannot detach from host cell and cannot be released Oseltamivir and Zanamivir Spectrum – Influenza A and B Used to reduce the severity and prevent the spread of influenza  Oseltamivir  Given orally  Excreted - urine - unchanged  Side effects - nausea and vomiting  Zanamivir  Inhaled  Excreted - urine - unchanged  Side effects – cough - nasal and throat symptoms Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Drugs for Hepatitis B and Hepatitis C Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Interferon α  Several available forms – α1, α2a, Pharmacokinetics  Injected subcutaneously  Peginterferons - interferon formulated with polyethylene glycol - longer t1/2 ➔ can be given once weekly Primary therapeutic option for:  Hepatitis B  Hepatitis C - when used in combination with Ribavirin Ribavirin - guanosine analogue that inhibits viral RNA polymerases Interferon α – Side Effects Side effects  Acute - flulike syndrome with headache, chills, fever, and muscle pain  Chronic use - adverse effects on all systems  Most common:  Alopecia, pruritus (itching), and rash  Weight loss  Bone marrow suppression  GI upset  Joint and muscle pain  Dizziness, headache, and insomnia  Anxiety, irritability, and depression Approved Indications for Interferons Interferons = endogenous cytokines Alpha - Interferes with viral replication ➔ Used as an antiviral Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Drugs for Hepatitis B and Hepatitis C Adefovir, Dipivoxil, Entecavir, Lamivudine, Telbivudine, and Tenofovir  These are alternative drug choices for the infection  Nucleoside/Nucleotide analogues that inhibit viral polymerases  Orally effective Side effects  Asthenia and nephrotoxicity (adefovir, dipivoxil [dose-dependent])  Dizziness, fatigue, headache, and nausea (entecavir)  Dizziness, headache, and nausea (lamivudine)  Headache, cough, fatigue, flu, and increased serum creatine kinase level (telbivudine)  Asthenia, rash, and GI upset (tenofovir) Summary - Drugs Used to Treat non-HIV Viral Infections Simmons Pharmacology: An Illustrated Review Therapeutic Management of HIV and AIDS What kind of virus is HIV? Therapeutic Management of HIV and AIDS  HIV is a retrovirus  Transmitted by free viral particles or infected immune cells (e.g., CD4 (helper T cells), macrophages, and dendritic cells) in blood, semen, vaginal fluid, preejaculate, and breast milk  It causes acquired immunodeficiency syndrome (AIDS) Therapeutic Goals in the Management of HIV and AIDS   CD4 cell counts  () suppress viral load  reconstitute the immune system Therapeutic Management of HIV and AIDS HAART = Highly Active Antiretroviral Therapy  Combination therapy used in the treatment of HIV/AIDS  Purpose - decrease the development of resistance It usually involves using three agents from two different classes Therapeutic Management of HIV and AIDS Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Combination Therapy has Improved Patient Outcomes US Statistics Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Replication of the HIV virus 1. Virus Attachment - Proteins (gp120 + gp41) on the surface of the HIV virus cell bind to CD4+ receptors (glycoproteins) found on the surface of helper T cells, monocytes, and macrophages. 2. Viral fusion - HIV RNA, reverse transcriptase, HIV integrase, and other viral proteins – free in the host cell upon uncoating 3. Uncoating ➔ Reverse transcriptase released and transcribes singlestranded viral RNA to double-stranded DNA in the host cell cytoplasm 4. Integration - New viral DNA migrates into the nucleus and becomes spliced into host DNA by the action of HIV integrase 5. DNA is transcribed into new viral RNA, which is then translated into viral proteins. 6. New viral RNA and proteins congregate near the cell membrane and become enclosed in the membrane, forming immature (not yet infective) HIV virions, which bud off from the host cell 7. Immature virions are cleaved by proteases into its mature, infective form Replication of the HIV virus Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy Pharmacological Management of HIV and AIDS Nucleoside Inhibitors of Reverse Transcriptase  Nucleosides containing an abnormal sugar moiety  Require phosphorylation for activation  As triphosphates - inhibit reverse transcriptase ➔induce strand breaks following incorporation into DNA Simmons Pharmacology: An Illustrated Review Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Nucleoside Reverse Transcriptase Inhibitors Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir Azidothymidine, AZT AZT The first antiretroviral drug approved by the FDA for HIV treatment  Orally effective Serious adverse effects for NRTIs can be:  pancreatitis  fatty liver  lactic acidosis  peripheral neuropathy Side Effects of NRTIs Simmons Pharmacology: An Illustrated Review Pharmacological Management of HIV and AIDS Nonnucleoside inhibitors of reverse transcriptase  DO NOT need activation  Bind near the active site of the viral reverse transcriptase ➔ inhibit activity Simmons Pharmacology: An Illustrated Review Nonnucleoside Reverse Transcriptase Inhibitors e.g. Delavirdine, Efavirenz, Etravirine, Nevirapine Can lead to hypersensitivity reactions and liver disease They are substrates of cytochrome P-450 enzymes ➔ prone to drug-drug interactions Efavirenz – Drug Facts Pharmacokinetics Side Effects and Precautions Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Pharmacological Management of HIV and AIDS Protease inhibitors  prevent polyprotein cleavage ➔ inhibit viral maturation Simmons Pharmacology: An Illustrated Review Protease Inhibitors Saquinavir, Ritonavir, Lopinavir, Indinavir, Nelfinavir, Amprenavir, Atazanavir, Tipranavir, and Darunavir Mechanism of action  Inhibit viral assembly and release from the host CD4 cells Pharmacokinetics  Inhibitors of CYP3A4 ➔ DDI risk Drugs that Should NOT be CoAdministered with HIV Protease Inhibitors FIX Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Drugs that Can be CoAdministered with HIV Protease Inhibitors BUT WITH CAUTION Lippincott’s Illustrated Reviews: Pharmacology, 6th edition General Side Effects of HIV Protease Inhibitors Changes in body fat distribution (central obesity, buffalo hump, gynecomastia) Lippincott’s Illustrated Reviews: Pharmacology, 6th edition Pharmacological Management of HIV and AIDS Fusion inhibitors  prevent attachment of viral proteins to host CD4 cells ➔ inhibit viral entry Simmons Pharmacology: An Illustrated Review Entry/Fusion Inhibitor - Enfuvirtide  Binds to the transmembrane glycoprotein subunit (gp41) of the viral envelope ➔ prevents the fusion of viral envelope and cell membrane ➔ prevents viral entry Chemokine Coreceptor Antagonist Maraviroc Maraviroc blocks certain strains of HIV from binding to chemokine receptor type 5 (CCR5) ➔ preventing viral entry No effect - in later stages of the disease Golan, Armstrong & Armstrong Principles of Pharmacology: A Pathophysiologic Basis of Drug Therapy Antivirals - Summary Katzung’s Basic & Clinical Pharmacology Potential Antiviral Treatments Can Target Different Steps of SARSCoV-2 Replication Virus Facts Hu et al. Nature Reviews Immunology October 2020 CONGRATS MD310 MATERIAL END HERE ALMOST – RHEUMATOID ARTHRITIS