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34 Cards in this Set
- Front
- Back
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What kind of molecule are most antiviral drugs?
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Nucleoside analogs.
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What is a prodrug?
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A drug administered in an inactive form. Nucleoside analogs are an example of a prodrug; they must be converted inside the cell sequentially by adding three phophates (converted to triphosphate).
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What is the mechanism of action for nucleoside analogs?
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They 1) inhibit nucleic acid polymerases (polymerase inhibitor) and 2) terminate the elongation of nucleic acid chains (chain terminator).
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What limits the efficacy of nucleoside analogs?
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They can only affect nascent chains; they cannot kill nonreplicating viruses. Therefore, they are not a cure.
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What are two differences between virus and host cell machinery that allow for drug specificity?
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1) Viruses and host cells use different enzymes for nucleic acid synthesis. 2) These enzymes have different affinities; viral enzymes are more promiscuous (ooooh~).
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What is the drug design of nucleoside analogs?
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They are acyclic nucleosides/(nucleotides). This means the ribose is broken, which allows for termination of the chain because elongation depends on a phophate being attached to the ribose.
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What are the 8 HHVs (Herpes simplex viruses)?
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*HHV-1: oral and facial (cold sores); *HHV-2: genital herpes; *HHV-3: varicella zoster (chickenpox and shingles); HHV-4: Epstein-Barr virus (infectious MONOnucleosis); *HHV-5: cytomegalovirus; HHV-6, 7: roseolovirus; HHV-8: Kaposi's sarcoma-associated herpevirus * -- tx
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Describe herpes viruses (DNA/RNA, size, enzymes).
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Herpes is a large DNA virus with 100-200 genes. It encodes its own viral DNA-dependent DNA polymerase.
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What is the role of thymidine kinase and which HHV's code for it?
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Thymidine kinase is an enzyme that allows growth in nondividing cells where thymidine monophosphate (TMP) is limiting. HSV 1, 2 and VZV code for it, but CMV does not (tx with a different drug group).
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What are the acyclovir congeners (derivatives) and how are they improved?
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Valacyclovir: ester with improved bioavailability; Penciclovir: same solubility, higher intracellular stability (longer half life); Famciclovir: ester of penciclovir
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Why does acyclovir cause crystalluria (crystals in urine) in pts who are not well hydrated?
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During the recovery of water in kidneys, acyclovir precipitates out because of its poor water-solubility.
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What drugs are used to treat herpes keratitis?
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Vidarabine, an adenosine analog with D-arabinose and uridine analogs- Idoxuridine and Trifluridine
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What drug is used to treat cytomegalovirus and what is it activated by?
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Ganciclovir: Acyclovir derivative. Activated by CMV-encoded kinase called UL97
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What is the toxicity of ganciclovir?
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Highly toxic, causes myelosuppression (reduced bone marrow activity. Severe neutropenia when used together with AZT (zidovudine).
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What 2 drugs bypass acyclovir resistance and how do they do this?
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Cidofovir and foscarnet, by bypassing the phosphorylation step by the viral kinase.
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What must be given with cidofovir and why?
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Prehydration and oral probenecid to block elimination of the drug in the kidney and maintain an artificially high concentration.
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What toxicity is associated with cidofovir and foscarnet?
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Renal toxicity. This is dose-limiting and patients must be well hydrated.
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What is the mechanism of foscarnet?
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It blocks the pyrophosphate binding site on viral DNA polymerase as an analog of pyrophosphate.
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What kind of virus is Hepatitis A? Is it a DNA or RNA virus?
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Hepatitis A virus is a picornavirus encoded by positive stranded RNA. There is no treatment and infection causes short-term liver illness.
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What kind of virus is Hepatitis B? What kind of DNA/RNA? What does it have that we target with drugs?
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A hepadnavirus with partially double-stranded circular DNA. The virus replicates using an RNA intermediate and reverse transciriptase. Therefore, we can target it with NRTIs = nucleoside analog reverse transcriptase inhibitors.
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What kind of virus is hepatitis C? DNA/RNA?
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A flavivirus encoded by positive-stranded RNA. The virus uses an RNA-dependent RNA polymerase.
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What do NRTIs do? What do they treat?
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Inhibit reverse transcriptase and stop elongation. HBV
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What is the problem with lamivudine?
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Viruses develop rapid resistance.
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What drug is used as an alternative to lamivudine? Why?
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Adefovir, bypasses resistance as nucleoTIDE analog. No resistance for up to 1 year; however high renal toxicity (fo).
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What kind of drug is interferon alpha? What does it treat?
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A cytokine: inhibits viral rep in infected cells and activates macrophages and NK cells. HBV and HCV - prophylactic and chronic.
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What are the contraindications for interferon alpha?
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Autoimmune dz and hepatic decompensation -- develops too much immunity. Also has toxicity (see chart).
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What drug is used with interferon alpha? What kind of drug is it?
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Ribavirin, not a monotherapy. It is a guanosine/adenosine dual analog.
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What is the mechanism for ribavirin?
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It inhibits RNA replication with hypermutation. It is NOT a chain terminator.
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What toxicity and contraindication is associated with ribavirin?
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Dose-limiting hemolytic anemia (RBCs store phosphorylated ribavirin). Pregnancy (teratogen)
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What kind of virus is influenza? DNA/RNA?
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Orthomyxovirus, negative-stranded RNA virus.
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What designates strains of influenza A? What does viral uncoating require? What enzyme does it use?
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Hemagglutinin (binds to sialic acid) for entering cells and Neuraminidase (cuts sialic acid) for exiting cells. Requires viral M2, hydrogen channel, to uncoat. Uses viral RNA-dep RNA transcriptase.
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What are the two M2 inhibitors?
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Amantadine and rimantadine.
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What kind of side effects are associated with amantadine and rimantadine?
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GI and CNS. Amantadine is more CNS-toxic bc crosses BBB.
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What are the two neuraminidase inhibitors?
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Oseltamivir and zanamivir.
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