Antivirals Flashcards
5-iododeoxyuridine and trifluorothymine were early antiviral agents that had poor ______ and were thus too toxic for systemic use, but are still used for topical treatment of ______
poor specificity- inhibited host and viral DNA
used for herpes keratitis
List viruses that can now be treated with antiviral therapies
herpes viruses HCV HBV papillomavirus influenza HIV
All antivirals are ______; they are active only against replicating virus and do not affect latent virus
virustatic
List some drugs that inhibit viral entry or penetration
fusion inhibitors, soluble receptor decoys, antireceptor antibodies, interferons
List some drugs that inhibit release of the viral genome (uncoating)
ion channel blockers, capsid stabilizers
List some drugs that inhibit viral transcription and replication of viral genes
viral DNA and RNA polymerase inhibitors, reverse transcriptase inhibitors, interferons
List some drugs that inhibit translation of viral mRNA into protein
interferons, antisense oligonucleotides
List a drug class that inhibits post-translational modifications
protease inhibitors
List a class of drugs that inhibit assembly of virion components
Interferons
List drugs that inhibit budding and release of virus
Neuraminidase inhibitors, interferons, antiviral antibodies, cytotoxic lymphocytes
Valacyclovir is a prodrug acyclic guanosine nucleoside analogue active against:
HSV-1 and HSV-2
VZV
EBV
Describe the mechanism of action of valacyclovir
Viral thymidine kinase (TK) converts acyclovir into acyclovir monophosphate; the monophosphate is then converted into the triphosphate form by cellular enzymes
Acyclovir triphosphate inhibits viral DNA synthesis by competitive inhibition of viral DNA polymerase and incorporation into the growing viral DNA chain, causing chain termination
What are adverse reactions to valacyclovir?
CNS, GI, nephrotoxicity
What precautions should be noted for use of valacyclovir?
renal insufficiency- dose reduction
What viruses is ganciclovir active against?
CMV (indicated for CMV retinitis)
weak activity against HSV, VZV
Describe the drug ganciclovir
Synthetic acyclic guanosine nucleoside analogue
mainly indicated for CMV retinitis
Describe the mechanism of action of ganciclovir
CMV kinase (UL97 gene) in CMV-infected cells converts ganciclovir to the monophosphate; the monophosphate is then converted into the triphosphate form by cellular enzymes
Ganciclovir triphosphate inhibits viral DNA synthesis by competitively inhibiting viral DNA polymerase and also causing eventual chain termination
________ is a drug that is CMV selective and has weaker activity against HSV and VZV strains
Ganciclovir
What adverse reactions to ganciclovir can be seen>
GI- NVD
Heme- cytopenias
What precautions should be noted with ganciclovir
bone marrow suppression
renal insufficiency
________ is an acyclic cytosine angalog active against CMV, HSV, adenovirus, and pipillomavirus. It is 60x more potent vs CMV and is indicated for CMV retinitis
cidofovir
Describe the mechanism of action of cidofovir
Inhibits viral DNA polymerase but does NOT require activation by viral kinase, so it is active against TK deficient or mutant strains
Works by competitively inhibiting viral DNA polymerase and causing chain termination
What is unique about the mechanism of cidofovir compared to ganciclovir and valacyclovir?
Cidofovir does not need to be activated by a viral kinase
List some of the adverse reactions to cidofovir
renal hemeatolgic opt derm GI fever, chills
What special precaution exists for cidofovir
Must prehydrate with a liter of normal saline with probenecid
______ is a synthetic thymidine nucleoside analogue with specific activity against HBV
telbivudine
Describe the mechanism of action of telbivudine
Phosphorylated by cellular kinase to a triphosphate
competitively inhibits HBV DNA polymerase by competing with D-thymidine
Incorporation into viral DNA leads to chain termination
What adverse reactions can be seen with telbivudine
fatigue, lactic acidosis, hepatomegaly with steatosis, peripheral neuropathy
-2, HIVWhat viral infections can be treated with interferons?
HBV, HCV, HSV-1 and HSV, HIV
What is the mechanism of action of interferons against viral infection
induce signal cascades that result in inhibition of viral penetration, translation, transcription, protein processing, maturation, and release, and they induce enzymes that cleave viral RNA
Also activate and enhance killing ability of NK cells and macrophages and have antiproliferative effects on tumor cells
What are precautions for interferon use?
hepatic dz
thyroid dz
autoimmune dz
________ is a purine analogue active vs many RNA and DNA viruses including HSV, VZV, and RSV
Ribavirin
Ribavirin is formulated with ____________ to treat HCV infections
interferon a-2b (Rebetron)
What is the mechanism of action of ribavirin?
Phosphorylated by cellular enzymes to the triphosphate; interferes with the synthesis of GTP by inhibiting IMPDH, inhibits viral RNA-dependent polymerase; increases the mutation rate of viral RNA to the point at which viable virions are not produced
Inhibits the replication of a wide range of DNA and RNA viruses, including influenza A and B, parainfluenza, RSV, paramyxoviruses, HCV, and HIV-1
What precautions exist for ribavirin?
Pregnancy risk X
monitor hematocrit
renal insufficiency
_______ is used for HCV genotype 1 infection in combination with peginterferon alpha and ribavirin
beceprevir
Describe the mechanism of action of beoceprevir
HCV NS3/4A serine protease inhibitor; binds to the NS3/4A active site serine (S139) through an α-ketoamide functional group; NS3/4A is necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of NS4A, NS4B, NS5A and NS5B proteins
How can resistance to boceprevir arise?
Resistance can arise from one or more amino acid substitutions in the NS3 protease domain
What precautions exist for boceprevir?
Not for monotherapy
Strong CYP inhibitor
________ is used for phrophylactic or symptomatic treatment of influenza esp in high risk patients, must be initiated within 48 hours of symptom onset, and potentiates DA transmission so can be used in Parkinson’s tx
amantadine
Describe the mechanism of action of amantadine
blocks the M2 proton channel within the viral membrane, preventing acid-dependent uncoating of viral capsid and release of viral RNA; inhibits influenza A virus replication by preventing release of viral RNA into host cell
Amantadine is specific for influenza ___
A
What precautions exist for amantatine
renal insufficiency
psychosis
narrow angle glaucoma
_______ is a sialic acid mimic that inhibits spread of influenza A and B and is used for tx and prophylaxis
oseltamivir
Describe the mechanism of action of oseltamivir
prodrug, hydrolyzed by hepatic esterases to the active form which competes with sialic acid for binding to the viral neuraminidase
Blocks the ability of neuraminidase to cleave sialic acid-containing receptors on the surface of the cell to which hemagglutinin binds
Result is an inability to release progeny virions from infected cells, thus halting the spread of infection
How can resistance to oseltamivir arise?
mutations in viral neuraminidase or hemagglutinin proteins
Oseltamivir prevents ______ of virus from cells
release
