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GI Exam 2
IBD Pharmacology/Med-chem
| Question | Answer |
|---|---|
| Review: How does Colestipol work? | increases the excretion of bile to help diarrhea |
| what are the 2 subtypes of IBD? | Ulcerative Colitis and Crohn's disease *both caused by inflammation |
| What does IBD stand for? | inflammatory bowel disease |
| In general is there more or less pro-inflamatory cytokines with IBD? | MORE |
| is this CD or UC? 1. TH1 and TH17 mediated? 2. TH2 and NKT-mediated? | 1. CD 2. UC |
| CD or UC: There is increased IL-12 | Both CD and UC |
| CD or UC: there is increased IL-23 | CD |
| CD or UC: there is increased IFN-y and TNF-a | Both CD and UC |
| What are the 2 classes of 5-ASA compounds? | Azo (N=N) compounds; Mesalamine compounds (contains Mesalamine and releasing formulations) |
| What meds are Azo (N=N compounds? | SOB (Sulfasalazine, Osalazine, Basalazide) |
| What is the MOA of 5-aminosalicylate (5-ASA) compounds? What effect does this have? | -activates (agonist) PPAR-y, nuclear Transcription factor *basically activating PPAR-y to turn down the inflammatory process -Decreases Pro-inflammatory cytokines (i.e IL-1, TNF-a) |
| Sulfsalazine can impair _____ absorption | folate |
| What is a possible consequence of 5-ASA looking similar to PABA? | Folic acid looks like PABA (our bodies need folic acid *Folic acid has so many polar groups that it should never get into our cells but we have specific transports bc our cells need this |
| Our cells need folic acid. The transporters latch to the PABA so if you put something else that looks like PABA (like 5-ASA) it will _____ with the transporters. So you may need to keep an eye on the level of folic acid bc you may need to supplement it | INTERFERE |
| All 5-ASA's have a CI to what and why? | hypersensitivity to aspirin bc they look similar to salicylic acid |
| Carvalho slide (5-ASA derivative)--> why are some considered prodrugs? | The only one where 5-ASA is completely free to go is MESALAMINE; -w/ others, 5-ASA is bound somehow and it needs to be released so technically its a prodrug |
| 5-ASA derivatives (some are prodrugs, only free one is Mesalamine), Prodrug derivatives have to be released/broken somehow to release the 5-ASA at the _____ | SOA; *one of the reasons why this is done, is to cut down on the systemic absorption bc you don't want this to be circulating in the body. you want it to stay in the intestines (very polar will be released to SOA (the intestines) |
| How could antacids affect the therapeutic effect of Asacol (a 5-ASA)? | Asacol has a pH sensitive release *programmed to release in the intestines where the pH is alkaline. If you tring antacis and making the STOMACH alkaline, Asacol will break apart before it should |
| T/F: Sulfasalazine is a prodrug | True |
| Why is sulfasalazine minimally absorbed? | -bc it has low solubility bc in the stomach it stays "clumped" if its clumped, it doesn't get absorbed very readily. Once it passes into the intestine, it gets a little more soluble in the higher pH so it "De-clumps" and it can go and get exposed to the membranes and do its thing. |
| The major source of breakage for these molecules to release 5-ASA is the ____ ________ meaning bacteria will break them apart and release the 5-ASA | Gut microbiome |
| Which functional group of Sulfasalazine will cause SE? | Sulfonamide |
| To be metabolized, Sulfasalazine needs to be _______ at the NITROGEN that is released from the azole group | acetylated *at the N=N group |
| So if a pt is a fast acetylator and takes sulfasalazine, will it get out of circulation quickly or slowly? More or less SE? | Quickly; Very little SE |
| So if a pt is a slow acetylator and takes sulfasalazine, will it get out of circulation quickly or slowly? More or less SE? | Slowly; more SE bc it will accumulate and keep circulating |
| Most compounds that contain sulfur or sulfonamide will have what 3 side effects? | Allergic rxn; agranulocytosis; increased sensitivity of skin to sunlight |
| Sulfasalazine will have hypersensitivities to salicylates and sulfonamides | True *salicylates (bc of the 5-ASA) |
| T/F: Osalazine is pretty much a dimer of 5-ASA | True *is essentially 2 molecules of 5-ASA linked together; once it gets to the intestine, it breaks apart into 2 5-ASA molecules |
| Which 5-ASA is the most active? | Osalazine *bc its a dimer of 5-ASA (essentially 2 molecules of 5-ASA linked together; Once it gets to the intestine, it breaks apart into 5-ASA molecules |
| What are the interactions of Osalazine? | 1. Heparin, warfarin (bc they depend on plasma binding and will compete for the sites where these drugs will be binding; 2. 6-MCP or 6-Thioguanine (increased risk of myelosuppression); *will cause inhibition of TPMT which is what metabolizes 6-MP so if you aren't metabolizing 6-MP, then you will see increased risk of Myelosuppression |
| Which 5-ASA has 2 5-ASA molecules bound to each other, forming a dimer? | Osalazine (twice as much 5-ASA, causing it to be the most potent |
| What are your glucocorticoid medications? | Prednisone; Prednisolone; Budesonide*; Hydrocortisone; Dexamethasone; Methylprednisolone *potent analog of prednisolone |
| What is the MOA of glucocorticoids? What specifically do they inhibit? | *Activates glucocorticoid receptors (which are nuclear receptors) -inhibits pro-inflammatory interleukins (NF-kB*, NOS, PLA2, AA, COX2 |
| AE to remember for Glucocorticoids is causing ______ _______ | Pituitary suppression (ACTH inhibtion) -others are insomnia, peptic ulcer, |
| Most potent Glucocorticoid is? | Dexamethasone |
| Anti-inflammatory potency to the equivalent dose: Hydrocortisone has an anti-inflammatory potency of ____ which makes the equivalent oral dose ____ mg | 1; 20mg |
| Anti-inflammatory potency to the equivalent dose: Prednisone has an anti-inflammatory potency of ____ which makes the equivalent oral dose ____ mg | 4; 5 mg |
| Anti-inflammatory potency to the equivalent dose: Prednisolone has an anti-inflammatory potency of ____ which makes the equivalent oral dose ____ mg | 5; 5 mg |
| Anti-inflammatory potency to the equivalent dose: Methylprednisolone has an anti-inflammatory potency of ____ which makes the equivalent oral dose ____ mg | 5; 4 mg |
| Anti-inflammatory potency to the equivalent dose: Dexamethasone has an anti-inflammatory potency of ____ which makes the equivalent oral dose ____ mg | 30; 0.75 mg (most potent requires the lowest dose |
| Why is it good that Budesonide )a glucocorticoid) undergoes extensive 1st pass metabolism in which the activity will be lost? | bc you dont want it circulating throughout your body; you want it to work directly at the intestinal wall; *so whatever escapes the intestinal wall and falls into systemic circulation is going to be destroyed in the first pass metabolism--> won't have much risk for systemic effects |
| Does Budesonide have active or inactive metabolites | Practically inactive metabolites *it contains a protected version of a ketone (very easy to break apart) and can form 3 metabolites (practically inactive) |
| What kind of reaction is mostly responsible for the first pass metabolism of Budesonide? | Hydroxylation as well as O-O via O-dealkylation |
| Because Budesonide tends to be a CYP3A4 ________, you have to be careful with other drugs that might be using this enzyme for their metabolism so you may need dose adjustments depending on what you are working with | Inhibitor |
| Which medications are TNF-a inhibitors? | I CAG Infliximab Certolizumab (CD) Adalimumab Golimumab (UC) |
| MOA of TNF-a inhibitors? | monoclonal antibody against tumor necrosis factor-a *antibodies can recognize soluble and Membrane-bound form of TNF-a |
| Uses of TNF-a inhibitors? | -prevents TNF-a stimulation of TNFR on immune cells (i.e. macrophages, helper T-cells) -sequesters that cytokine TNF-a (to prevent from binding to the receptor) *doesn't directly impact TNF-a -Decreass proinflmmatory cytokine release, decreases T-cell proliferation, endothelial adhesion molecules |
| Main interaction/Comments to know about TNF-a inhibitors: Certolizumab does ____ stimulate antibody-induced apoptosis/cell death; Not recommended b/c similar effect to _____; will also see increased lymphoma risk + other immunomodulators | NOT; Placebo |
| Certolizumab pegol, which is pegylated, does what to clearance? | Pegylation delays clearance *will circulate in the body longer bc it is very water soluble si ti will help to stay suspended in the blood stream and bc its connected via a steric ester bond; these esterases take awhile to break the bond b/w the antibody and the pegylated molecule--> so you have a SLOW RELEASE EFFECT |
| Which medication is an integrin inhibitor? | Vedolizumab and Natalizumab (Spears notes very restricted use) |
| What is the MOA of Vedolizumab? | Monoclonal antibody against integrin ADHESION molecules -prevents inflammatory cell binding to endothelial tissue in the intestine -decreases the interaction of inflammatory cells with gut tissue |
| Which medications have a BBW of progressive multifocal leukoecephalopathy (PML)? | Vedolizumab and Natalizumab (Integrin inhibitors) *rare, reactivaiton of John Cunningham virus in CNS; > greater risk with Natalizumab (US Boxed warning), restricted use for Natalizumab |
| Carvalho integrin receptor antagonists: Vedolizumab (Entyvio) and Natalizumab (Tysabri) MOA: | Binds to integrin molecules on surface of T and B lymphocytes and prevents their binding to GI mucosal cell adhesion molecules (CAM), preventing migration into the gut; IV infusions |
| Which medications are interleukin inhibitors? | Ustekinumab; Guselkumab; Mirikizumab; Risakizumab |
| What is the MOA of Ustekinumab? | Monoclonal antibody against IL-12 and IL-23 |
| MOA of Guselkumab, Mirikizumab, Risakizumab? | Monoclonal antibody against IL-23 *specifically targeting IL-23); P-19 subunit *decreases activation of NK cells, TH1 cells |
| What are the interleukin inhibitors used for? | Moderate to severe CD and UC |
| What medications are Janus Kinase inhibitors? | Tofacitinib and Upadacitinib |
| MOA of JAK inhibitors? effect? | selective JAK inhibitor -decreases phos-STAT (a transcription factor) formation |
| Uses for JAK inhibitors? | decreases TNF-a expression; decreases T-cells, B-cells, NK differentiation |
| what are the 2 molecular units of a Janus? | 1. Kinase (part that phosphorylates things) 2. regulator *two faced roman god; these work together |
| Why are JAK inhibitors potent immunosuppressants? | bc it kind of looks like some of our purines so it can mess with DNA transduction of our immune cells *suppress intracellular signaling mediated by multiple cytokines involved in the pathological processes of immune and inflammatory diseases by interfering w/ the ATP-binding site of JAKs |
| What mediations are non-biologic: S1P receptor modulators? | Etrasimod and Ozanimod |
| MOA of Etrasimod and Ozanimod (S1P receptor modulators)? effect of their MOA? | Sphingosine 1-phosphate (S1P) modulators; decreases lymphocyte egress/migration out of the lymph nodes (it keeps the lymphocytes w/in the lymph nodes so that they don't go on to activate other immune cells) *decreases release of S1P lymphocytes |
| Etrasimod and Ozanimod share the _____ and the _____ | S1P 1 and 5 *Etrasimod binds to S1P 1,4,5 *Ozanimod has a high affinity for S1P 1,5 |
| What part of Etrasimod's structure causes it to accumulate in retinal cells? | double bonds all over the structure (*carotoid long tail) *twists and turns on structure represent the polar carbonic tails, can also accumulate in the liver |
| Which medications are immunomodulators: Purine analogs? MOA? | Azathioprine and 6-mercaptopurine; purine antimetabolites (*mimic structure of purine) *inhibits DNA and RNA synthesis; Inhibit T-cell production (fast-growing cells) |
| what is the use of Azathioprine and 6-MP? | suppresses T-cell proliferation and DNA/RNA replication |
| What is the big ADR of Azathioprine and 6-MP? | Bone marrow suppression |
| Pts on Azathioprine or 6-MP need adequate ______ activity | TPMT (thioprine-S-Methyltransferase) *want to check this so that you can confirm that your pts can properly metabolize 6-MP *if a pt's TPMT isn't working well--> can cause bone marrow suppression |
| If a pt is on Azathioprine or 6-MP, you can lower the dose of the _____ if needed | steroid |
| What is the drug interaction b/w allopurinol and Azathioprine or 6-MP? | allopurinal and febuxostat are XO inhibitors; XO metabolizes 6-MP so if you inhibit this, then you will get an increase in azathioprine and 6-MP |
| _____ needs to be transformed into something that looks like a nucleotide before it can actually work and if you inactivate it before it transforms into a nucleotide, you will kill the drug | Mercaptopurine *too much activity on TPMT may degrade the drug before it can do something to little activity; you can have excess that can cause toxicity |
| Azathioprine is a pro-drug that needs to break to release _______. | Mercaptopurine |
| Olsalazine and allopurinol inhibit TPMT. How will that affect drug therapy? | it will increase concentrations of azathioprine and 6-MP since they aren't getting metabolized |
| Why should azathioprine and mercaptopurine not be used concurrently? | can increase risk of infection |
| Which meds are immunomodulators: Calcineurin inhibitors: | Cyclosporine and Tacrolimus |
| MOA of our calcineurin inhibitors: Cyclosporine and Tacrolimus is? | Both inhibit (aka decrease) Calcineurin activation of NF-AT transcription factor -causing a decrease in gene transcription |
| Why do you have to give Cylcosproine and Tacrolimus with micro emulsions to give it orally? (2 reasons) | They are highly polar (so they dont like to be absorbed); They are all oligopeptides, so uf you throw something like that in your stomach w/o some sort of protection, it will be destroyed. *Microemulsions help to get to the SOA |
| why is Cyclosporine and tacrolimus nephrotoxic? | Because they are POLAR -if you ahve a highly polar drug, it starts ACCUMULATING--> messing with kidney cells |
| How does having one or both non-functional TPMT alleles affect drug therapy? | having one or both non-functional TPMT alleles Significantly Increases the Risk of Severe Bone Marrow Suppression when taking thiopurine drugs like Azathioprine or mercaptopurine, as the body cannot properly metabolize these meds due to reduced enzyme activity |
| Why does Cyclosporine have a wide extravascular distribution? | highly polar; our body has efflix pumps that through drugs away and cyclosproine really likes to activate those pumps--> so our cells want to get rid of it as soon as possible--> will have a lot circulating in the plasma and very little accumulating in the cells |
| What is the MOA of MTX? | inhibits dihydrofolate reductase, competitive and irreversible -decreases thymidine and purine production to block DNA and RNA synthesis -stimulates increased adenosine release |
| What are the AE of MTX? | bone marrow suppression* others are alopecia, anemia, (high doses), drug accumulation with renal insufficiency |
| use of what with MTX lowers the risk of AE of bone marrow suppression? | folic acid |
| T/F: MTX interferes with the formation of DNA | True |
| In regard to the chemical rxn, what gets added on when you add folic acid on with MTX? | adds on a methyl group |
| T/F: MTX can increase liver enzymes | True *bc liver is pumping out more enzymes to metabolize it |
| ______ supplementation is necesary to reduce incidence of MTX-related AE | Folate |
| DDI of MTX: what happens when you take NSAIDS with MTX? | decreases MTX elimination by inhibiting the organic anion transporters in the kidneys |
| what abx are given for IBD? | Metronidazole and Cipro |
| What is the MOA of Metronidazole and Cipro for IBD? | Metabolites accumulate and destabilize DNA molecules -used to inhibit bacterial activity -goal is still to reduce immune cell activity |
| What is Metronidazole used for? Cipro is used for? | bactericidal activity of anaerobic bacteria -DNA gyrase inhibition; breaks DNA strands |
| T/F: Metro and Cipro are typically adjunctive with other IBD meds | True *not used alone |
| SE of Metronidazole? | metallic taste, disulfuram-like effect if taken with alochol |
| T/F: Metro is a prodrug | True |
| What part of the structure of Cipro is responsible for the BBW of tendon rupture, inflammation, limit use in pregnant and children; mysethenia gravis (may exacerbate muscular weakness, rash, photosensitivity) | O=C-C-C=O *calcium can also chelate here |
| Why shouldn't we take Cipro after taking an antacid? | because the antacid will chelate to the C=O groups |
| Why do we use abx against IBD? | -evidence suggests that gut bacteria play a role in Crohn's disease -Chronic intestinal inflammation may be cuased by abnormal immune respose to normal flora in genetically susceptible hosts |
| Excessive amounts of this IBD tx can cause pituitary suppression? | Prednisolone (or any glococorticoid) |
Created by:
Xander635
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