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75 Cards in this Set
- Front
- Back
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What are most antiviral drugs to date?
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Nucleoside drugs
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What are most nucleoside drugs?
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prodrugs...converted to triphosphate inside cells..
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MOA of Nucleoside -
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inhibit nucleic acid polymerases (polymerase inhibitor)
terminate the elongation of nascent nucleic acid chain (chain terminator) |
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What is limitation of nucleoside?
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Affect only nascent chains and cannot kill non replicating viruses (not a cure)
so can't stop herpes virus thay lay dormant |
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Acyclovir
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Guanosine analog
Actv - converted to acyclo MP by viral thymidine kinase (tk); converted to acyclo-DP and acyclo-TP by cellular kinases.. |
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Characteristics of nucleoside drugs
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require intracellular activation to triphosphate to work
Are poly inhibitors/chain terminator Block synthesis of nascent acid chains Have higher affinity to viral enzymes than cellular compartments Acyclic drugs embody the best understood design concept |
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What are characteristics of Herpes virus?
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Large DNA virus with 100-200 genes
DNA replication by viral DNA-dependent DNA polymerase HSV and VZV code for thymidine kinase (tk) to allow growth in non-dividing cells where TMP is limiting |
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What is TMP?
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Thymidine mono-phosphate
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CMV does/doesn't have thymidine kinase
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doesn't
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What is MOA of acyclovir?
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Acyclo-TP inhibits viral DNA polymerase
It is also a chain terminator (terminator is not removable) |
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Mechanism of drug selectivity for Acyclovir
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affinity to acyclovir - Viral Tk > cellular TK (3000x)
affinity to acyclovir-TP: viral DNA poly > cellular DNA pol (100x) |
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Mechanism of drug resistance to Acyclovir
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gene mutations in tk and/or viral DNA pol
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How is drug resistance for Acyclovir produced?
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gene mutations in tk and or/viral DNA pol
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What is pharmacokinetics for Acyclovir?
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oral, topical, and IV
Poorly water soluble and poor bioavailability Short half life due to rapid intracellular degradation |
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How is Acyclovir eliminated?
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Renal elimination (in its intact form)
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What is toxicity for acyclovir?
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generally well tolerated
crystalluria following iv injection if patient not well hydrated |
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Who are Acyclovir congeners?
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Valacyclovir
Penicyclovir Famicyclovir |
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What is benefit of using valacyclovir over acyclovir?
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acyclovir ester with improved oral bioavailability
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Pencicyclovir benefit -
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higher intracellular stability (longer intracellular half life); not an obligated chain terminator
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Famicyclovir benefit -
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ester of penicyclovir with improved oral bioavailability
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vidARABine
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adenosine analog with with a D-arabinose
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Activation of vidarabine
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viral TK to form ara-AMP
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MOA of vidarabine
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ara-ATP inhibits viral DNA polymerase but it is NOT a chain terminator
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Resistance to vidarabine
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yes, but mostly due to mutation in DNA polymerase
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What is clinical use of vidarabine
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topical treatment of herpes keratitis
Can't be used orally due to rapid metabolic inactivatin and high genetic toxicity |
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What are some other drugs used for herpes keratitis?
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IdoxURIDINE and triFLURIDINE - uridine analogs
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Why can't we use acyclovir for CMV?
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because it doesn't have thymidine kinase
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Ganciclovir
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derivative of acyclovir by one side chain
( has two things instead of one) |
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MOA of genciclovir
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activated by a CMV encoded kinase called UL97
MOA same exact as acyclovir |
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Resistance of genciclovir
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mutation in UL97 or viral DNA polymerase
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Pharmacokinetics of genciclovir
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poor oral bioavailability
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What drug is similar to genciclovir and what's the benefit of using it
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valganciclovir - an ester so improved bio availability
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Main side effect of genciclovir
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myelosuppression - severe neutropenia when used together with AZT (zidovudine)
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Characteristic of HBV
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hepadnavirus that replicates using an RNA intermediate and a reverse transcriptase just like HIV (only hepatitis that does this) so we can use an NRTI
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What are some drugs used for HBV?
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Lamiduvine
Adefovir dipivoxil Interferon-alpha |
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Lamiduvine -
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a cytidine analog
NRTI - chain terminator and blocks reverse transcriptase |
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MOR of Lamiduvine
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Rapid resistance - mutation in reverse transcriptase; occurs in 20% of cases in 1 year
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Kinetics of Lamiduvine
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Oral; renal excretion
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Toxicity of Lamiduvine -
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non toxic for HBV dose
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Adefovir dipivoxil constituent
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diester prodrug for adefovi
(NRTI - AMP analog like Cidofivir, a CMP analog) Dipivoxil - improves oral bioavailability by increasing solubility |
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MOR of Adefovir
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Slow resistance; no resistance for upto 1 year (advantage vs. Lamiduvine)
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Kinetics of Adefovir
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oral; renal excretion
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Toxicity of Adefovir
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Dose limiting renal toxicity
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WHat is DOC for HCV?
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Interferon alpha
Other - ribavarin +RNA dependent RNA polymerase |
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What is interferon alpha?
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recombinant protein or its derivative with polyethylene glycol ( for longer half life)
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MOA for INF alpha
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cytokine (non specific) that binds to specific cell-membrane receptors to induce gene expression
Inhibits viral replication inside infected cells by interfering with viral replication cycle stimulates systemic immune responses by activating macrophages and NK cells |
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Kinetics for INF alpha
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subcutaneous or intramuscular injection. drug in serum is filtered and proteolytic degraded in kidneys.
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What is benefited of using pegylated form of INF alpha
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conjugated with ethylene glycol so can lost longer and only injected once weekly
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Toxicity of INF alpha
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pyrogen, so fever and flu like symptoms -
injection site tissue damage (due to macrophages and NK cells) Bone marrow suppression at high doses - interferes with prodn of bone marrow cells |
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Who can INF alpha be not given to?
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autoimmune diseases, hepatic decompensation
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Uses of INF alpha?
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HBV
prophylactic treatment of suspected HCV and for t/x of chronic hep c |
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Ribavarin -
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guanosine/adenosine dual analog
monotherapy not effective; approved for use adjunctively with INF alpha |
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MOA of Ribavarin -
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inhibits DNA replication by "genetic meltdown" - hypermutation
NOT a chain terminator |
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Kinetics of Ribavirin
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oral; renal elimination
RBCs store phosp form over lifetime |
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Toxicity of Ribavirin -
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hemolytic anemia - dose limiting
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Whom can Ribavarin be not given in?
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Pregnancy - teratogen
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Adefovir - nucleotide/nucleoside?
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nucleotide analog
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Char of Influenza A virus
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affects humans and birds
negative stranded RNA virus Viral RNA dependent RNA transcriptase DOES NOT PROOF READ |
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What are two proteins Influenza virus codes for that helps in infection?
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Hemagglutinin - for entering cells by binding to sialic acid
Neuraminidase - cuts sialic acid - leaving infected cells |
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What is one key component reqd by Influenza virus A in uncoating?
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viral M2, an H+ channel
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What are most drugs targeted against in Inf A infection?
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against H/M
not against rev transcriptase |
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What are 2 M2 inhibitors?
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aMANtidine and riMANtidine
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What is chemistry of M inhibitors?
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adaMANtane derivatives -- not nucleoside drugs
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Mechanism of M2 inhibitors..
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M2 inhibitor..duh!
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What can M2 inhibitors be used for?
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prophylaxis and treatment of suspected influenza A infection
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Can Influenza A be resistant to M2 inhibitors?
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yes, because of hyper mutation of virus
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Kinetics of M2 inhibitors
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oral; renal eliminated (aMANtidine) and liver metabolized and renal eliminated (riMANtidine)
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toxicity of M2 inhibitors
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CNS and GI effects - nausea and dizziness
Amantidine causes more s/e than rimantidine.. Overdose amantidine can cause hallucinations, arrhythmias, and death |
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Examples of neurAMIdinase inhibitors
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Tamiflu - oseltAMIvir
zanAMIvir |
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Chemistry of neurAMIdinase
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sialic acid analogs
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MOA of neurAMIdinase inhibitors
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neurAMidinase blockers
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Use of neurAMIdinase inhibitors
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prophylactic and treatment for both - Inf A & B
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Resistance of neurAMIdinase inhibitors?
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Cross resistance is easily possible
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Kinetics for neurAMIdinase inhibitors -
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oselTAMIvir - orally
zanAMIvir - inhaled renal elimination |
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Side effects of neurAMIdinase inhibitors -
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GI irritability for oseltAMIvir
bronchospasm for zanAMIvir |
