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GI Final 3
Spears and Carvalho Hep C
| Question | Answer |
|---|---|
| Hep C is a viral infection that causes ______ and eventually severe ______ _______ | inflammation; liver damage |
| Treatments for Hep C are going to be associated with trying to reduce the symptoms and treat with antiviral medications and ultimately a _____ _______ is what would be necessary. | liver transplant |
| In the presence of the Hepatitis C virus, we start to see ____ of the liver which of course will then make it difficult for signaling and for the liver to conduct its function | scaring |
| In End stage liver disease, we can even see _______ tissue develop | cancerous |
| Viral infection process consists of? | Attachment--> Penetration--> Uncoating --> RNA/DNA synthesis--> Transcription--> translation /replication--> Packaging/Assembly--> Release |
| Be sure to highlight the "6th step" known as _____ ______ _______. This is the step that is going to be targeted by our medications to inhibit translation and replication of the viral proteins | Virus Protein Synthesis |
| When it comes to Hep C we know that its one of the ___ strains of hepatitis | 6 *A, B, C, D, E, G |
| Hep C is a ____-_____ pathogen with Hepatitis __ being the most prevalent worldwide and subtypes 1a and 1b having variation in what countries have expression of Hep 1a and 1b, and the subtypes can also differ in their responsiveness to antiviral medication | blood-borne, 1 |
| Its important to know that Hepatitis C is a (+) ____- ______ RNA virus and that its made up of structural and *non-structural proteins | single-strand |
| Non-structural proteins is highlighted because those are the ones that are ______ by the medications that we'll talk about | inhibited |
| Hep C is a capsid molecule and each of the proteins that make up this capsid encoded by this _____. Blue portion on slide 6 represents the ______ ______ | "RCV" Hepatitis C RNA; structural proteins |
| Each of the proteins (slide 6) would have to be synthesized by the host cell for it to be packaged and release the viral protein but the ones that are targeted by our medications are going to be? | NS3/NS4; NS5A; NS5B *so we can have individual drugs or a combination of drugs that prevent the formation of those non-structural proteins such that the HCV genome cannot properly assemble and will disrupt the replication of the Hepatitis C |
| Hepatitis C Life Cycle--> Uses the machinery of the host cell to cleave these particular areas of the HCV genome in order to make each of the particular proteins and once transcribed can form new viral _____ or ______ | molecules or proteins |
| Slide: Direct Acting Antiviral DAA) Treatments: Important portion that our drugs target are the _____-_______ proteins of the HCV (Hepatitis C virus) genome | non-structural |
| What are the drugs that target the NS3/4 serine protease inhibitors? "end in "previr" | Paritaprevir; Voxilaprevir; Grazoprevir; Glecaprevir |
| What are the drugs that inhibit the NS5A (non-structural protein)? "end in asvir" | Ledipasvir; Ombitasvir; Velpatasvir; Elbasvir; Pibrentsavir |
| What are the drugs that target the NS5B named RNA polymerase Inhibitors? 1 is a nucleoside analog and the other is a non-nucleoside analog. "ends in buvir" | Nucleoside analog (Sofosbuvir) Non-nucleloside analog (Dasabuvir) |
| Non-structural proteins of the Hepatitis C virus genome contain which proteins that are targets for our medications? | p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B |
| Our primary medications that we see are going to be those inhibitors of "Group C" labeled as? (slide 9) | Inhibitors of non-structural proteins (primary) |
| Other therapeutic agents for Hepatitis C Virus are grouped as? | A. Immunomodulators (historical); B. Nucleoside analog (adjunctive); C. Inhibitors of non-structural proteins |
| Medications in group A for Immunomodulators (historical) that we may see are? | PEG-interferon-alpha 2a (Pegasys); PEG-interferon-alpha 2b (Pegintron) |
| Medications in group B for Nucleoside analog (adjunctive) that we may see is? | Ribavirin (Rebetol, Copegus) |
| Medications in group C for Inhibitors of non-structural proteins (primary) that we may see are? | Grazoprevir; Elbasvir; Sofosbuvir (Sovaldi) *these are Direct acting antiviral (DAA) treatment against HCV aka Specifically targeted antiviral therapy for HCV (STAT-C) |
| For the combination therapeutic Agents for Hepatitis C virus, we will be tested on the: | components of each |
| Combination Therapeutic Agents for Hepatitis C virus: What are the components of Epclusa? | Sofosbuvir (NS5B + Velpatasvir (NS5A) |
| Combination Therapeutic Agents for Hepatitis C virus: What are the components of Harvoni? | Ledipasvir (NS5A) + Sofosbuvir (NS5B) |
| Combination Therapeutic Agents for Hepatitis C virus: What are the components of Mavyret? | Glecaprevir (NS3/4A) + Pibrentasvir (NS5A) |
| Combination Therapeutic Agents for Hepatitis C virus: What are the components of Vosevi? | Sofosbuvir (NS5B) + Velpatasvir (NS5A) + Voxilaprevir (NS3/4A) |
| Combination Therapeutic Agents for Hepatitis C virus: What are the components of Zepatier? | Elbasvir (NS5A) + Grazoprevir (NS3/4A) |
| PEG-interferons are "general immunomodulators) *remember that pegylation will? | increase the 1/2 life |
| What are the drugs of our PEG interferons? | Pegylated interferon a2a; Pegylated interferon a2b |
| What is the MOA of our PEG interferons? | Binds cell surface interferon receptors; antiviral, anti-proliferative and immunomodulatory actions *they can bind to either host cell receptors or the viral proteins as well |
| What our PEG interferons do is they disrupt the viral replication process of these viral proteins but considering that they can act on the host cell, it could have a potential for serious adverse effects, one of them being? | causing hyperbilirubinemia (excess bilirubin in the blood) and can also lead to auto-immune hepatitis |
| Our PEG interferons are commonly combined with _____ | Ribavirin |
| MOA of Ribavirin is not well understood, but exam wise it inhibits? Use of Ribavirin is to inhibit the replication of? | HCV polymerase; HCV and can also apply to both RNA and DNA viruses *this is the NS5B (first portion of the non-structural protein genome) |
| Ribavirin has several boxed warnings which are? | Monotherapy is INEFFECTIVE (remember its combined with other Non-structural protein inhibitors) Hemolytic anemia--> MI; -Pregnancy teratogenic/embryocidal effects |
| Med-Chem Ribavirin--> They look like "Nucleotides and that's their MOA." They fool the organism into thinking that they are the ____ _____ that are building the viral RNA to think they are incorporating nucleotides and its actually incorporating that _____ _____ | Viral proteins; Faulty structure (which breaks the whole sequence) |
| Med-Chem Ribavirin--> structure: what we have is the triazole ring mimicking enough that the polymerase think its the right thing and tries to incorporate it. It incorporates the bottom -OH groups to form the ______ | polymer, but when it comes time to be transcribed, it wont work because its not fully recognized by the machinery |
| Med-Chem Ribavirin--> oral BA is decent, its water-soluble. but due to all the mechanisms of transportation that's recognized nucleotides to bring them inside the cell, this drug will be very much ________ in the tissues | concentrated *Carvalho circles the D: Vd 2859 L --> concentrated in tissues bc again it looks like a nucleotide and is brought into the cell (reason why we have so many SE (not just messing with the transcription of the virus but ours as well |
| Med-Chem Ribavirin--> Metabolism: Hydrolysis of the amide to form a carboxylic acid and to remove it from the ____ | Body (and the removal of this ribose (sugar part) so once it break apart, the whole nucleotide structure disappears, the body doesn't do anything with it anymore |
| "Previr" drugs inhibit NS3/4A protease. List the drugs? Use? | Grazoprevir; Glecaprevir; Voxilaprevir; Antiviral agents, Chronic HCV |
| AE of our "Previr" drugs that inhibit the NS3/4A protease? Comments? | Pruritis, rash, Photsensitivity, Nausea, Hyperbilirubinemia (by inhibition of OATP1B1/3); Comments: inhibits viral replication and assembly |
| "Asvir" drugs inhibit NS5A. List the drugs? Use? | Elbasvir; Pibrentasvir; Ledipasvir; Velpatasvir; Antiviral agents, Chronic HCV |
| AE of our "Asvir" drugs that inhibit NS5A? Comments? | Fatigue, HA, Nausea, Anemia, Hyperbilirubinemia; Comments: Inhibits RNA replication and virion assembly |
| "Buvir" drugs inhibit NS5B. List the drug? Use? | Sofosbuvir; Antiviral agents, Chronic HCV |
| AE of our "Buvir" drugs that inhibit NS5B? Comments? | Diarrhea, Anemia, HA, Insomnia, Fatigue, Increased bilirubin levels Comments: Inhibits viral replication |
| Med-Chem: "Previr" drug interactions include? | Strong CYP 3A4 and P-GP inhibitors; CYP substrates |
| Med-Chem: "Asvir" drug interactions include? | Ledipasvir--> 3a4 inducers, antacids (decreases absorption) |
| Med-Chem: "Buvir" drug interactions include? | Sofosbuvir is a P=glycoprotein (P-GP) substrate; Inducers of P-GP can decrease sofosbuvir exposure and loss of activity (i.e rifampicin, St. John's wort) |
| Med-Chem: -Previr, -Asvir, and -Buvir PK--> they are very similar in terms of ______ _______ in terms of Vd. Metabolism is mostly ______. And they may be influenced by other inhibitors of CYP's so be mindful of drug interactions. | protein binding; Hepatic |
| Med-Chem: Structural vs non-structural proteins, what's up with that? Structural is? | what builds, what shows when the virus is circling around the RNA, the capsid, whole machinery that allows the virus to do its thing |
| Med-Chem: Structural vs non-structural proteins, what's up with that? Non-Structural is? | are the ones that will build the whole virus *think of it like the virus is the finished dress; proteins being synthesized are the fabric. Those proteases are the scissors that will be cutting into the shapes they need to be |
| Building mechanism is based on Serine meaning they hinge on a serine amino acid in their ____ _____ which catalyzes the whole breakage of those proteins | active site |
| Again, Structural proteins are being produced by the KNOWN STRUCTURE into this big piece of tape that needs to be cut. To cut, the Proteases need to? | recognize the right parts |
| Mimic the orignal drug but have differences on (right side of slide 16) P1 where you have this highly _____ head that you just bind to your protease. stops the process because the real ________ cannot get there | polar; substrate *it works because it looks like the molecule that the enzyme is looking for |
| Med-chem: All of our NS3/4A protease inhibitors (Grazoprevir, Glecaprevir, and Voxilaprevir all have the same structural feature which is this big _____ group that will mimic what the enzyme is trying to cut. | polar *think of it as putting rubber on your scissors, so you can't close the scissors but they don't cut anything. drugs are sitting on top of the cutting edge of your proteases |
| Med-Chem: Our Polymerase inhibitors (NS5A -asvir) look like dimers and (Pibensavir) looks like amino acids and these things bind to two sides of the pyrimidine and act like a mechanical ______ of the enzyme | plugging *they interfere with both sides of the polymerases (the one that captures the amino acids and the one that uses the original RNA as a model) |
| Med-Chem: the only (-buvir) that we have (Sofosbuvir) is essentially a ______. It needs to be phosphorylated, so it needs to first remove (left of the phosphate group) and then gets incorporated into the growing _____ | prodrug; RNA |
| Med-Chem: -Buvir (incorporation into the RNA)--> but when it comes time to be transcribed, you have instead of a double -OH which is what you expect to see in your nucleosides, you have this ____ group. Why? | Flourine; *Highly electronegative; for the enzyme it will look like an oxygen but it wont work since the -OH is not there |
| Med-Chem: Sofosbuvir: (Ext 1st pass metabolism to form the ____ ____ which gets incorporated into the growing RNA; *most important metabolism reactions to remember are? | nucleotide phosphate *phosphorylation (makes it active; dephosphorylation makes it inactive) |
| HCV summary: remember the viral entry and replication by multiple sites of action for therapeutic drugs but with our HCV medications they will target and prevent the ______ process | replication |
| Some of our medications such as the interferons can? | boost the immune system response but they can also mimc nucelosides and majority of the medications will block those proteases in order to prevent formation of those non-structural proteins |
| Combination therapy is used to cover different targets for best _____ | efficacy |
| Protease inhibitors can inhibit ____ enzymes and ____ causing significant drug interactions | CYP; P-Gp |
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Xander635
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