PM 716 C49 Antivirals Slides PDF

PM 716 Pharmacology I Chapter 49 Antivirals, Antiretrovirals RMRocco, PhD PM716 C49 Antivirals 1  Terms I Antivirals 1. Herpes = Gr herpein, to creep 2. Varicella = “a tiny spot” 3. Zoster = Gr. girdle, 4. Virus = L. poison 5. Virion = complete vi...

PM 716 Pharmacology I Chapter 49 Antivirals, Antiretrovirals RMRocco, PhD PM716 C49 Antivirals 1  Terms I Antivirals 1. Herpes = Gr herpein, to creep 2. Varicella = “a tiny spot” 3. Zoster = Gr. girdle, 4. Virus = L. poison 5. Virion = complete virus particle with genetic material, with proteins. PM716 C49 Antivirals 2  Antivirals: Drug Targets 1. Entry into host cell. 2. Uncoating of viral nucleic acid. 3. Synthesis of regulatory proteins. 4. Synthesis of DNA or RNA 5. Synthesis of structural proteins. 6. Assembly of viral particles. 7. Release of new virus from host cell. PM716 C49 Antivirals 3 Chapter 49 Antiviral Agents PM716 C49 Antivirals 4 © The McGraw-Hill Companies, Inc,  Herpes DNA Virus Types 1. Herpes simplex (cold sores, genital infections) 2. Varicella-Zoster (chicken pox, shingles) 3. Cytomegalovirus (CMV) 4. Epstein-Barr (mononucleosis) 5. Herpes Virus Type 6 (roseola) 6. Herpes Virus Type 7 PM716 C49 Antivirals 5 Acyclovir, First Antiviral 1. Structure/Source: synthetic guanosine derivative. A guanosine look-alike. Guanosine monophosphate PM716 C49 Antivirals 6  Acyclovir 2. Mechanism of Action: (a) Viral thymidine kinase phosphorylates drug to acyclovir monophosphate (MP). Provides specificity, host cell can not monophosphorylate. (b) Host cell enzymes phosporylates to acyclovir DP and then acyclovir TP, the active form. (c) AcTP inhibits DNA synthesis by competitive inhibition with deoxyGTP for viral DNA polymerase, chain elongation ceases. PM716 C49 Antivirals 7  Acyclovir 3. Pharmacokinetics: F is about 15-20% following po dose. Used iv and topical for herpetic lesions. Cleared mostly by renal. 4. Antiviral Activity: HSV-1, HSV-2, VZV PM716 C49 Antivirals 8  Acyclovir 5. Clinical Uses: genital herpes, reduces frequency and severity of symptoms, does not eliminate virus. 6. Adverse Effects and ADR’s: Daily po dose (400 - 800 mg) for up to 10 years not associated with untoward effects. PM716 C49 Antivirals 9  Acyclovir 7. Mechanism of Resistance: mutation in viral thymidine kinase (decreased expression) or the viral DNA polymerase. Cross resistant to all similar drugs occurs also. PM716 C49 Antivirals 10 Chapter 49 Antiviral Agents PM716 C49 Antivirals 11 © The McGraw-Hill Companies, Inc, Chapter 49 Antiviral Agents PM716 C49 Antivirals 12 © The McGraw-Hill Companies, Inc,  Other Similar Antivirals Valacyclovir: a prodrug of acyclovir, the L- valyl ester of acyclovir. Metabolized to parent with higher Cp levels. Famciclovir: diacetyl ester prodrug of 6- deoxypenciclovir, a guanosine analog. First pass conversion to peniclovir, a drug very similar to acyclovir. Intracellular drug levels are higher with peniclovir. PM716 C49 Antivirals 13  Other Similar Antivirals Penciclovir: active metabolite of famciclovir Docosanol: 22 carbon saturated aliphatic alcohol, inhibits fusion between membrane and the HSV envelope, blocking viral entry into cells, topical cream without prescription, used at onset of prodromal symptoms. PM716 C49 Antivirals 14 Ganciclovir for CMV 1. Structure/Source: a synthetic guanosine analog. 2. Mechanism of Action: CMV specific protein kinase phosphotransferase UL97 phosphorylates drug. Inhibit DNA synthesis. PM716 C49 Antivirals 15  Ganciclovir 3. Pharmacokinetics: po, iv or intraocular implant. CSF levels post iv 50% of Cp levels. Clearance linearly related to CC. 4. Antiviral Activity: most herpes virus but 100 times greater activity against CMV compared to acyclovir. PM716 C49 Antivirals 16 Chapter 49 Antiviral Agents PM716 C49 Antivirals 17 © The McGraw-Hill Companies, Inc,  Ganciclovir 5. Clinical Uses: delay CMV retinitis in AIDS patients, high dose reduces risk of CMV infection from organ transplant. 6. Adverse Effects and ADRs: myelosuppression (neutropenia in 20-40% of patients), abnormal liver function tests. PM716 C49 Antivirals 18  Ganciclovir 7. Mechanism of Resistance: mutations in the UL97 phosphorylation enzyme resulting in decreased levels of active triphos drug. PM716 C49 Antivirals 19  Additional Drugs used for CMV Foscarnet: inorganic pyrophosphate drug that inhibits viral DNA polymerase, activation not required. IV only. This one is very unique among all the herpes antiviral drugs. PM716 C49 Antivirals 20  Avian Influenza Pandemic = influenza strain to which large numbers of the population are not yet exposed. Avian Influenza = Bird Flu = Influenza A (H5N1) Pandemic of 1918, > 50 million dead. Strains H1N1 “swine flu” was the cause of the first influenza pandemic PM716 C49 Antivirals 21 Anti-Influenza Drug Oseltamivir (Tamiflu®) (oh sel TAM i vir) 1. Structure/Source: synthetic analog of sialic acid (starting material from Chinese Herbal Medicine, Anise Star). PM716 C49 Antivirals 22 Oseltamivir (Tamiflu®) 2. Mechanism of Action: potent inhibitor of viral neuraminidase enzyme on viral surface. Enzymatic cleavage required for release of new virus from host cell. PM716 C49 Antivirals 23 3. Pharmacokinetics: drug exists phosphorylated prodrug that is cleaved to carboxylate active form. F = 80% po dose, cleared unmetabolized by kidney. 4. Antiviral Activity: treatment of influenza virus A and B. PM716 C49 Antivirals 24  Oseltamivir (Tamiflu®) 5. Clinical Uses: 75 mg twice a day for five days to treat the flu, reduces illness by 1-2 days. Reduces the incidence of hospitalizations by 50%. As prophylaxis, reduces incidence of illness by up to 90%. 6. Adverse Effects and ADRs: Mostly GI in 10- 15% of patients. 7. Mechanism of Resistance: mutation in the neuraminidase enzyme (0.5 to 5.5% of isolates). PM716 C49 Antivirals 25  Anti-Influenza Agents Zanamivir: a second neuraminidase inhibitor Amantadine & rimantadine: both drugs are tricyclic amines that block a proton ion channel in virus and prevents virus replication PM716 C49 Antivirals 26  Anti-hepatitis Agents Interferon Alfa (a cytokine) Binds to host cell and triggers cell actions that disrupt viral replication. A protein that is injected im or sc. Pegylated interferon alpha, the addition of polyethylene glycol to the drug increases its mw and prolongs the drug’s time in the body. PM716 C49 Antivirals 27  Hepatitis B (HBV) Adefovir dipivoxil: prodrug of adefovir Prodrug that becomes adefovir, an adenine analog, by human esterase enzyme Adenine nucleotide analog Inhibits HBV DNA polymerase which inhibits DNA synthesis Can cause lactic acidosis, related possibly to inhibition of mitochondrial DNA polymerase. PM716 C49 Antivirals 28  Hepatitis C (HCV) Polymerase Inhibitors: sofosbuvir, nucleotide analog inhibits HCV RNA polymerase Protease Inhibitors: boceprevir, inhibits HCV protease which prevents viral development Guanosine Analog ibavirin: guanosine analog inhibits synthesis of guanosine triphosphate, phosphorylated by host cell PM716 C49 Antivirals 29  Antiretroviral Drugs Worldwide infection with HIV, 42 million 20+ different drugs available in the US 3 drug combination is standard of care 1140 possible drug regimens/combinations Two major families of HIV HIV-1 most common HIV-2 found mostly in West Africa PM716 C49 Antivirals 30  HIV Entry into Host Cells 1. Virus attaches to CD4 receptor on surface through spike protein (gp120). 2. Virus envelop fuses with CD4 outer membrane (CD4 and Co-Receptor required). 3. RNA injected into the cell. 4. HIV reverse transcriptase converts viral RNA into DNA. PM716 C49 Antivirals 31  HIV Entry into Host Cells 5. DNA is spliced into CD4 host DNA by HIV integrase. 6. CD4 cell converts all of its DNA into mRNA (using human enzymes). mRNA moves to cytoplasm where it forms template for new proteins. 7. New HIV proteins assemble into new virus particles. HIV proteases chop proteins required for assembly. 8. New HIV particles released, host cell dies. PM716 C49 Antivirals 32  HIV PM716 C49 Antivirals 33 Chapter 49 Antiviral Agents PM716 C49 Antivirals 34 © The McGraw-Hill Companies, Inc,  HIV Major Target Host Cells CD4 Lymphocyte (T-Helper Cell) Stimulate plasma cells to make antibodies Stimulate Antigen Presenting Cells (APC) to engulf bacteria Stimulate other cells to produce cytokines. PM716 C49 Antivirals 35  CD4 Cells in Human Blood Reference Range (CD4) 1000/uL OR CD4 cells 1 000 000/mL Total # CD4 Receptors 52 000/CD4 cell OR 5.2 x 1010 CD4 Receptors/mL HIV virus/mL 100 000 particles/mL One HIV Virus has 520 000 CD4 receptors to choose from for cell entry. PM716 C49 Antivirals 36 Co-Receptors For HIV Entry CCR5 (macrophages) and CXCR4 (T-Cells) are chemokine receptors on cell surfaces. Co-receptor required for virus entry into the cell. PM716 C49 Antivirals 37 Variola major (Smallpox virus) Variola virus uses same CD4 and co-receptor to enter host cells. Mutations in co-receptor may explain some forms of HIV resistance: Homozygous: no entry Heterozygous: delayed entry. PM716 C49 Antivirals 38  HIV Antibody Screening All tests are for the Antibody, not the virus. PM716 C49 Antivirals 39  HIV Antibody Confirmation Western Blot HIV GP proteins bound to Membrane, patient serum on top, Antb if present will bind and be detected. The “Confirmation” method for HIV infection. PM716 C49 Antivirals 40  HIV Infection Monitoring Total CD4 cells reference interval 500 - 1200/uL HIV infection (non-treated) 350/uL AIDS < 200/uL Plasma HIV Viral Load reference interval 0/mL HIV InfectionPM716 C49 Antivirals 25 - 100 000/mL 41  Major Targets of HIV Drugs 1. Block the fusion of virus with CD4 receptor. (Fusion Inhibitors) 2. Inhibit HIV nucleoside reverse transcriptase (NRT) and block viral DNA formation (NRTI’s and NNRTI’s) HIV has 9 genes that code for 15 proteins. 3. Block the protease enzyme that forms new HIV virus (Protease Inhibitors). PM716 C49 Antivirals 42  HAART Highly Active Antiretroviral Therapy Goal of HAART: Lower HIV Plasma viral load levels to < 50 copies/mL Raise CD4 levels by 175 to 200/uL after 48 weeks of treatment. (Note: raise by, not to). PM716 C49 Antivirals 43 Fusion Inhibitors (Entry Inhibitor) (Enfuvirtide, Fuzeon®) en FYOO vir tide 1. Structure/Source: Synthetic 36 amino acid peptide. FDA approved March 2003. 2. Mechanism of Action: Binds to gp41 subunit of HIV viral envelop glycoprotein. Blocks conformational change in virus required for entry into cell. PM716 C49 Antivirals 44  Enfuvirtide (Fuzeon®) 3. Pharmacokinetics: sc only (a peptide), t1/2 = 3.8 h, in clinical trials mean - 1.7 log10 copies/mL reduction in HIV virus load, 90 mg dose, twice a day by sc injection. 4. Antiviral Activity: HIV-1 human virus 5. Clinical Uses: Adjunct to HAART therapy. 6. Adverse Effects and ADRs: None reported. 7. Mechanism of Resistance: None reported so far. PM716 C49 Antivirals 45  Maraviroc Used when patient’s HIV is resistant to more common drugs Drug binds to CCR5 co-receptor on CD4 cells (that’s different) Only good for CD4 cells with CCR5 receptor and not the CXCR4 co-receptor. PM716 C49 Antivirals 46 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 1. Structure/Source: Synthetic thymidine analog (zidovudine (Retrovir®) (AZT). 11+ FDA approved. Thymidine zye DOE vyoo deen PM716 C49 Antivirals 47  NRTIs 2. Mechanism of Action: Drugs inhibit viral reverse transcriptase which converts viral RNA into cDNA. Drugs lack 3’ hydroxy group which terminates DNA elongation. 3. Pharmacokinetics: Drugs are prodrugs, intracellular kinases phosphorylate drug into active compound, the triphosphorylated compound. Dose tid 200 mg po. NOTE: only intracellular active drug levels correlate with efficacy. PM716 C49 Antivirals 48  NRTIs 4. Antiviral Activity: Specific inhibition of viral reverse transcriptase. 5. Clinical Uses: Block viral replication. 6. Adverse Effects and ADRs: myelosuppression, headache, insomnia, myopathy, anxiety, confusion, anorexia, fatigue, nausea, malise. PM716 C49 Antivirals 49  NRTIs 7. Mechanism of Resistance: mutations in reverse transcriptase enzyme. HIV genotyping now required for all isolates. PM716 C49 Antivirals 50 NRTIs Didanosine (Videx®) an adenosine analog, with same mechanism of actions as others in the same class. Adenosine PM716 C49 Antivirals 51  NRTIs Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine PM716 C49 Antivirals 52 NRTIs 11 approved drugs 9 single 1 double 1 triple Wide variation in dose (0.75 mg to 300 mg) tid or bid. PM716 C49 Antivirals 53 Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) 1. Structure/Source: synthetics with wide variation in structure. Delavirdine de la VIR deen Efavirenz (Sustiva®) e FAV e renz PM716 C49 Antivirals 54  NNRTIs 2. Mechanism of Action: bind to active site on reverse transcriptase, induce conformational change in enzyme (inactivates). 3. Pharmacokinetics: Do not require phosphorylation for activation. 4. Antiviral Activity: Active against HIV1 only. PM716 C49 Antivirals 55 NNRTIs 5. Clinical Uses: Adjunct drugs in HAART therapy. 6. Adverse Effects and ADRs: inducers of CYP 3A4 which lowers Cp of other drugs. 7. Mechanism of Resistance: same. PM716 C49 Antivirals 56  NNRTIs Delavirdine Efavirenz Etravirine Nevirapine Rilpivirine PM716 C49 Antivirals 57 Protease Inhibitors (PIs) 1. Structure/Source: Synthetic peptidomimetic hydroxylamines with a wide variety of structures. Indinavir 2. Mechanism of Actions: Inhibit HIV viral protease. PM716 C49 Antivirals 58  PIs 4. Mechanism of Action: HIV viral protease has two 99 amino acid monomers. Human proteases have only one peptide chain which accounts for the specificity of the HIV viral PIs. 5. Antiviral Activity: HIV1 6. Clinical Uses: Adjunct in HAART therapy PM716 C49 Antivirals 59  PIs 6. Adverse Effects and ADRs: altered body fat distribution (Buffalo Hump). All PIs biotransformed by CYP 3A4 enzymes. Effects of meals on AUC after po dosing varies from a 600% increase in Cp to a 77% decrease in Cp levels. PM716 C49 Antivirals 60  PIs 6. Adverse Effects and ADRs: Reduced renal function requires dosage adjustments to prevent toxicity. PIs bound up to 98% to alpha-1-acid- glycoprotein (AAG). AAG levels vary from 54-70% between patients. Other drugs displace PI from AAG, rise in free Cp levels. PM716 C49 Antivirals 61  PIs Atazanavir at a za NA veer Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir PM716 C49 Antivirals 62  PIs Other drugs inhibit CYP3A4 which increase Cp levels. Ritonavir increases PI levels 20 fold. Amprenavir decreases PI levels 18% St. John’s Wort decreased AUC of PI by mean 57% and Cp by 81%. Cp of PIs correlate with toxicity and efficacy and reduced incidence of resistance. PM716 C49 Antivirals 63  PIs 7. Mechanism of Resistance: Altered protease enzyme PM716 C49 Antivirals 64  Integrase Inhibitors These drugs bind to viral integrase which inhibits strand transfer, thus blocking “integration” of reverse-transcribed HIV DNA into the chromosome of host white cells. dolutegravir PM716 C49 Antivirals 65  Ingtegrase Inhibitors Dolutegravir Elvitegravir Raltegravir Note all end in “gravir” PM716 C49 Antivirals 66  HAART Therapy At least two different NRTIs 1 or more PIs 1 Fusion Inhibitor (FI) (for nonresponders) Result: > 20 pills per day with wide variation in dose, frequency of dosing, food and ADRs variations. PM716 C49 Antivirals 67  Causes of Drug Failure 1. Sub-therapeutic Cp levels fail to suppress viral load (replication). 2. Lack of compliance (> 20 pills/day) 3. Drug resistance. 4. Individual difference in metabolism and clearance. 5. Drug-Drug and Drug-Food interactions. PM716 C49 Antivirals 68  HIV Drugs Required NRTs: zidovudine zye DOE vyoo deen lamivudine la MI vyoo deen tenofovir te NOE fo veer PM716 C49 Antivirals 69  HIV Drugs Required NNRTs delaviridine de la VIR deen nevirapine ne VYE ra peen PM716 C49 Antivirals 70  HIV Drugs Required Protease Inhibitors saqunavir sa KWIN a veer indinavir ritonavir PM716 C49 Antivirals 71  HIV Drugs Required Entry Inhibitors (Fusion Inhibitors) enfuvirtide en FYOO vir tide maraviroc mah RAV er rock PM716 C49 Antivirals 72  HIV Drugs Required Integrase Strand Transfer Inhibitors raltegravir ral TEG ra vir PM716 C49 Antivirals 73  Preparations Available Drugs in Bold are Required NRTIs abacavir didanosine emtricitabine lamivudine stavudine tenofovir zidovudine (AZT) PM716 C49 Antivirals 74  NNRTIs delavirdine efavirenz etravirine nevirapine rilpivirine PM716 C49 Antivirals 75 HIV Drugs PM716 C49 Antivirals 76  Case Study 35-year old female HIV and HBV positive, on methadone for heroin addiction, CD4 cell is 278/uL, viral load (HIV RNA) 110 000 copies/mL. Check renal function and for pregnancy. Use tenofovir and emtricitabine because both treat HIV and HBV. Add efavirenz if patient not pregnant. Monitor methadone, increase in dose may be required. PM716 C49 Antivirals 77