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39 Cards in this Set
- Front
- Back
Neuraminidase inhibitors
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- prevent release of virus
- Oseltamivir, Zanamivir |
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Oseltamivir and Zanamivir
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- Effective against type A and type B influenza
- admin prior to exposure --> prevent infection - admin w/in 24-48 hrs after infection --> modest effect - MOA = analog/inhibitor of sialic acid substrate for neuraminidase --> inhibit release of virus |
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Oseltamivir and Zanamivir - PK/AE
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PK
Oseltamivir - orally active prodrug (hydrolyzed in liver) Zanamivir - NOT orally active (inhaled, intranasal) AE - Oseltamivir - GI discomfort, nausea (alleviated w/ food) - Zanamivir - NO GI effects, Airway irritation (AVOID in severe asthma, COPD) |
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Oseltamivir and Zanamivir - Resistance
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- less infective + virulent neuraminidase mutations identified
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Ion channel blockers
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- prevent uncoating of virus in the cell
- Amantadine and Rimantadine |
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Amantadine and Rimantadine
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- Exclusively active on Influenza A virus
- MOA - Blocks viral membrane protein, M2 (H+ channel) - channel is required for fusion of viral w/ cell membrane --> endosome (required for viral uncoating) - "A man to dine" takes off his coat |
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Amantadine and Rimantadine - PK
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- oral
- amantadine - widely dist, crosses BBB (rimantadine is NOT), NOT extensively metabolized and excreted into urine where it may accumulate - Rimantadine IS metabolized and eliminated by the kidney |
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Amantadine and Rimantadine - AE
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Amantadine - CNS: insomnia, dizziness, ataxia --> hallucinations, seizures
Rimantadine - fewer problems Both - GI intolerance |
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Amantadine and Rimantadine - Contraindications and Resistance
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CI: monitor in psychiatric pts, cerebral atherosclerosis, renal impairment, epilepsy
CI: PREGNANCY, NURSING Resistance - Up to 50%; cross-resistance w/ other drugs also occurs |
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Purine/pyrimidine analogs
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- prevent RNA/DNA synthesis
- Ribavirin |
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Ribavirin
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- Active against broad spectrum of RNA and DNA viruses (eg RSV, HCV, Lassa fever)
- guanosine analog |
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Ribavirin - MOA
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- converted to ribavirin-triphosphate --> inhibits guanosine triphosphate formation --> prevents viral mRNA capping --> inhibits RNA-dep RNA polymerase
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Ribavirin - PK
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- Oral, IV, aerosalized
- absorption increased if taken w/ fatty meal - drug retention in all tissues except brain - drug/metabolite eliminated in urine |
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Ribavirin - AE/CI
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AE - dose-dependent transient anemia (can bind to RBC), elevated bilirubin
CI: PREGNANCY |
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Treatment of Hepatic Viral Infections
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Interferons
- Interferon alpha, beta, gamma Nucleotide/Nucleoside Analogs - Lamivudine, Adefovir, Entecavir, Telbivudine ALL inhibit RNA/DNA synthesis |
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Interferons
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- Naturally occurring, inducible glycoproteins/cytokines, alpha and beta produced by man cell types, gamma by immune cells (T cells)
- MOA: Use innate immune response; DO NOT target viral gene products directly - Inhibit RNA and DNA synthesis by activating/inducing protein expression that inhibit virus infection (eg PKR) |
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Interferons - PK/AE
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PK
- NOT orally active (IV, subcut, intralesionally) - cell uptake and met by liver and kidney --> little in plasma - usually pegylated to improve PK profile AE - Flu-like (fever, chills, myalgias + GI disturbances) - Fatigue + mental depression |
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Interferons - Drug Interactions/Clinical Applications
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Drug Interactions
- interferes w/ hepatic drug metabolism --> toxic acc of theophylline - may potentiate myelosuppression caused by zidovudine Clinical App: - interferon alpha: HCV, HBV, condyloma acuminata, hairy-cell leukemia, Kaposi's sarcoma - interferon beta - MS |
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Lamivudine, Adefovir, Entecavir, Telbivudine
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- must be phosphorylated to triphosphate (active) form
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Lamivudine
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- comp inhibits HBV DNA polymerase
- well absorbed orally + widely dist (half-life = 9h) - excreted unchanged in urine - well tolerated |
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Adefovir
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- incorp in viral DNA --> termination of DNA syn
- admin once daily, excreted in urine (45% active compound) - discontinuation --> severe exacerbation of hepatitis (25%) - used cautiously with renal dysfunction |
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Entecavir
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- competes w/ deoxyguanosine triphosphate for viral reverse transcriptase
- effective against lamivudine-resistant strains of HBV - very little metabolized - renal function must be assessed and drugs w/ renal toxicity avoided - monitor after discontinuation --> poss severe hepatitis |
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Telivudine
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- NOT effective against HIV or other viruses
- either competes w/ endogenous thymidine triphosphate or incorporates into viral DNA --> terminate DNA chain elongation - oral once a day - eliminated unchanged by glomerular filtration |
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Tx of Herpesvirus Infections
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- eg cold sores, viral encephalitis, genital infections
- herpes can form latent infection; available drugs are for REPLICATING VIRUS ONLY - Purine/pyrimidine Analogs: Acyclovir, Cidofovir, Ganciclovir, Penciclovir, Famiclovir, Vidarabine, Trifluridine - Fomivirsen - Foscarnet |
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Acyclovir
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- Prototypic antiherpetic therapeutic agent
- HSV Types 1 and 2, VZV, some EBV (HSV4) - DOC IN HSV ENCEPHALITIS - also used for genital herpes infections and prophylactically in IC and transplant pts |
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Acyclovir - MOA
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- Guanosine analog
- Monophosphorylated by HSV/VZV thymidine kinase --> only infected cells susceptible - Competes w/ dGTP; once incorp into DNA causes chain termination and INHIBITS VIRAL DNA POLYMERASE |
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Acyclovir - PK
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- IV, oral, topical
- well dist (INCLUDING CSF) - partially metabolized --> urine (can acc w/ renal failure) |
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Acyclovir - AE/Resistance
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AE: depends on route of admin:
- topical = local irritation - oral = headache, diarrhea, nausea, vomiting - renal dysfunction at high doses Resistance - **altered or deficient thymidine kinases** and DNA polymerases (most commonly in IC) - cross resistance to other cyclovirs |
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Cidofovir
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- HSV, adenovirus, CMV-induced retinitis in HIV/AIDS
- NOT phosphorylated by viral kinases - REQUIRES ACTIVATION BY HOST CELL KINASES - effective against HSV and Ganciclovir resistant orgs - MOA: DNA chain terminator and DNA polymerase inhibitor |
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Cidofovir - PK, AE, Resistance
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PK: IV, intravitreal, and topical
- must be co-admin w/ probenecid (blocks renal tubular secretion) AE: nephrotoxicity Resistance: mutations in viral DNA polymerase |
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Ganciclovir
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- Valganciclovir = pro-drug w/ greater oral bioavailability
- Analog of acyclovir (8-20X activity against CMV) - DOC FOR CMV RETINITIS + CMV PROPHYLAXIS IN IC - MOA - phosphorylated by viral and cell kinases; DNA chain terminator and DNA polymerase inhibitor |
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Ganciclovir - PK
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- IV, well dist (including CSF)
- excretion in urine via glomerular and tubular secretion - valganciclovir undergoes rapid hydrolysis in intestine and liver --> ganciclovir |
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Ganciclovir - AE/CI/Resistance
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AE: myelosuppression, severe, dose-dependent neutropenia
CI: PREGNANCY Resistance: reduced intracellular phosphorylation (mutations in phosphotransferase) or mutations in viral DNA polymerase |
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Famciclovir and Penciclovir
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- Famciclovir - pro-drug of penciclovir
- active against HSV-1,2 and VZV - MOA: inhibit HSV DNA polymerase / chain terminator - PK: Penciclovir - only topical (half life is 20-30 times acyclovir triphosphate); Famciclovir - oral - AE: Headaches, nausea, diarrhea - Resistance - Low occurrence clinically |
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Vidarabine
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- Adenine analog
- effective against HSV, CMV, VZV - limited to tx of IC pts w/ herpetic and vaccinal keratitis + HSV keratoconjunctivitis - MOA: inhibits viral DNA synthesis after conversion to triphosphate - PK - opthalmic ointment - AE: superficial punctate keratitis, pain, photophobia |
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Trifluridine
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- Thymidine analog
- Effective against HSV-1,2 and vaccina virus - DOC FOR HSV KERATOCONJUNCTIVITIS AND RECURRENT EPITHELIAL KERATITIS - MOA - incorporated into viral DNA causing fragmentation - PK: ophthalmic ointment (too toxic for systemic use) - AE: transient irritation of eye + palpebral (eyelid) edema |
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Fomivirsen
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- Antisense oligonucleotide
- USED WHEN OTHER THERAPIES FOR CMV RETINITIS FAIL - MOA - bind to CMV mRNA inhibiting CMV protein synthesis - PK: intravitreally; long half-life - AE: iritis, vitritis, changes in vision and changes in intraocular pressure |
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Foscarnet
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- organic analog of inorganic pyrophosphate (does NOT require phosphorylation)
- "FOScarnet = pyroFOSphate analot" - used for CMV retinitis in IC pts, acyclovir resistant HSV and CMV retinitis, gancyclovir-resistant CMV + VZV - MOA: selectively inhibits virus-specific DNA polymerase and reverse transcriptase - PK: IV (poor oral abs), widely dist including CNS |
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Foscarnet: AE/Resistance
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AE
- Nephrotoxicity, hypocalcemia - CNS: hallucinations, seizures Resistance - Point mutation in polymerase |