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35 Cards in this Set
- Front
- Back
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GI System- Agents Used in Inflammatory Bowel Disease by Maloney
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GI System- Agents Used in Inflammatory Bowel Disease by Maloney
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Ulcerative colitis vs. Crohn’s disease
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UC: type 2 helper T cell predominate
-resticted to colon, continuous lesion, superficial layers Crohn's: Type 1 helper T cell predominate, any part of GI tract, patchy lesions, superficial and deep layers |
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Inflammatory Bowel Disease Drug Classes
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5-Aminosalicylates
Antibiotics Corticosteroids Immunosuppressive Agents Biological Response Modifiers |
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Where do prostaglandins and leukotrienes come from?
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arachidonic acid
cyclooxygenase turns AA into prostaglandins, and 5-lipoxygenase turns AA into leukotrienes How can you prevent the damaged caused by excess prostaglandins and leukotrienes in patient with IBD? -give a drug that inhibits cyclooxygenase and 5-lipoxygenase |
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What agent will block both cyclooxygenase and lipoxygenase?
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5-amino salycylic acid (ASA)
aka Mesalamine |
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5-Aminosalicytes Agents, oral and rectal
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Oral:
Sulfasalazine (Azulfidine) Olsalazine (Dipentum) Balsalazide (Colazal) Mesalamine (Asacol, Pentasa, Lialda, Apriso) Rectal (for distal colon lesions): Mesalamine rectal suppository (Canasa) Mesalamine rectal enema (Rowasa) *they all contain the active component 5-ASA |
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5-Aminosalicytes MoA...where does it need to be to be effective?
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Exact mechanism is unknown
Topical effect on the GI tract Block the production of leukotrienes by inhibiting 5-lipoyxgenase |
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90% of an oral dose of 5-ASA will be absorbed in the upper GI and metabolized
How do you prevent systemic absorption of these drugs? |
Rectal delivery methods:
-Mesalamine rectal suppository (Canasa) -Mesalamine rectal enema (Rowasa) Delayed (pH) and/or sustained (Time) release delivery methods: -Mesalamine (Asacol, Pentasa, Lialda, Apriso ) Conjugated to a carrier that is released in the colon: -Sulfasalazine – carrier is sulfapyridine -Olsalazine – carrier is another molecule of 5-ASA -Balsalazide – carrier is an inert molecule |
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What do you need to do in order to free a drug from the carrier?
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break the azo bond connecting the two. Bond is cleaved by bacterial azoreductase in the colon
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Where in the GI tract will the different 5-ASA formulations be released/effective?
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rectal enema- distal colon
azo bond- lower intestine asacol (pH)- distal and lower SI pentasa (time)- SI and LI |
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5-Aminosalicytes Agents, oral and rectal
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Oral:
Sulfasalazine (Azulfidine) Olsalazine (Dipentum) Balsalazide (Colazal) Mesalamine (Asacol, Pentasa, Lialda, Apriso) Rectal (for distal colon lesions): Mesalamine rectal suppository (Canasa) Mesalamine rectal enema (Rowasa) *they all contain the active component 5-ASA |
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5-Aminosalicytes MoA...where does it need to be to be effective?
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Exact mechanism is unknown
Topical effect on the GI tract Block the production of leukotrienes by inhibiting 5-lipoyxgenase |
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90% of an oral dose of 5-ASA will be absorbed in the upper GI and metabolized
How do you prevent systemic absorption of these drugs? |
Rectal delivery methods:
-Mesalamine rectal suppository (Canasa) -Mesalamine rectal enema (Rowasa) Delayed (pH) and/or sustained (Time) release delivery methods: -Mesalamine (Asacol, Pentasa, Lialda, Apriso ) Conjugated to a carrier that is released in the colon: -Sulfasalazine – carrier is sulfapyridine -Olsalazine – carrier is another molecule of 5-ASA -Balsalazide – carrier is an inert molecule |
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What do you need to do in order to free a drug from the carrier?
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break the azo bond connecting the two. Bond is cleaved by bacterial azoreductase in the colon
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Where in the GI tract will the different 5-ASA formulations be released/effective?
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rectal enema- distal colon
azo bond- lower intestine asacol (pH)- distal and lower SI pentasa (time)- SI and LI |
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5-Aminosalicytes Clinical use
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Mild to moderately active ulcerative colitis
-Induce remission -Maintenance of remission Mild to moderately active Crohn’s disease -Ileocolonic or Colonic involvement -Induce remission (questionable) -Maintenance of remission (questionable) *5-ASA compounds have the best evidence for inducing remission with CD |
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Sulfasalazine Adverse effects are dose dependent. this includes:Nausea
Vomiting Headache Epigastric pain Malaise Male infertility what is this due to? |
due to sulfapyridine released. hypersensitivity rxns from the suflapyridine released include:
Fever Skin rash Hemolytic anemia Agranulocytosis Pulmonary complications Hepatitis Pancreatitis* (5-ASA may contribute) *folic acid deficiency (so may take supplement) |
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Mesalamine/Olsalazine/Balsalazide AE
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Headache
Dyspepsia Skin rash Diarrhea (Especially Olsalazine) Nephrotoxicity |
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Antibiotics Agents
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Metronidazole
Ciprofloxacin Rifaximin |
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Antibiotics MoA, clinical use
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MoA
-Unclear -Reduce intestinal bacteria -Directly suppress the intestine’s immune system -Metronidazole is the most extensively studied antibiotic for Crohn’s disease Use: -Mild to moderately active Crohn’s disease --Induce remission; Maintenance of remission (questionable) -Perianal Crohn’s disease -Fistulizing Crohn’s disease -Abscesses from Crohn’s disease -*Not effective for ulcerative colitis |
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Corticosteroids Agents
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Prednisone
Methyprednisolone Hydrocortisone (Rectal enema or foam) Budesonide (Entocort EC) Antiinflammatory agents! |
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What is the main problem with the use of corticosteroids (especially long term)?
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you become the steroid man.
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Budesonide (Entocort EC)
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Controlled ileal release formula
High affinity for the glucocorticoid receptor 80-90% is eliminated by first pass metabolism in the liver (doesnt get into systemic circulation a whole lot) works topically. |
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What is the potential
advantage of budesonide vs. prednisone? |
less side fx. but you do get steroid sfx and it doesnt work much better.
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Corticosteroids clinical use
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Moderate to severely active ulcerative colitis or Crohn’s disease
-Oral, rectal, or parenteral -Induce remission -Prolonged use in steroid dependent patients Not effective for maintaining remission Budesonide shown to prolong the time to relapse in patients with Crohn's disease in medically induced remission |
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Steroid groups
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1.Steroid responsive:
-Clinical improvement 1-2 weeks -Remain in remission when drug tapered slowly over weeks or months 2.Steroid dependent: -Clinical improvement 1-2 weeks -Relapse when steroid dose is tapered 3. Steroid unresponsive If a person is unresponsive to steroids, or is steroid dependent, or has severe disease and goes into remission with steroids, what else can you do? if it's not serious, give 5-ASA. only give if it's at most moderate |
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Immunosuppressive Agents, clinical use
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Thiopurine analogs
-Azathioprine (Imuran) -6-Mercaptopurine (Purinethol) Methotrexate Cyclosporine (Sandimmune, Neoral) For inducing remission in patients unresponsive to steroids For reducing steroid use in patients that are steroid dependent For maintenance therapy in severe IBD after inducing remission with steroids Fistulizing Crohn’s disease |
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AZA/6-MP, MTX, Cyclosporine onset of benefit and use
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AZA/6-MP: 3-6months; UC or CD, induce remission, maintenance
MTX: several weeks; CD, induce remission, maintenance Cyclosporine: 1-2 weeks, UC or CD, induce remission |
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Immunomodulators Cautionary Note
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They can have significant toxicity, even when used carefully
It is imperative to understand their potential toxicity and how to appropriately monitor patients to ensure safety |
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Biological Response Modifiers
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-Tumor necrosis factor-a (TNF-a) inhibitors
-Selective adhesion-molecule inhibitors |
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TNF-a inhibitors
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Infliximab (Remicade)
Adalimumab (Humira) Certolizumab Pegol (Cimzia) Monoclonal antibodies to tumor necrosis factor-a (TNF-a) |
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TNF-a antibodies MoA
What is the difference between infliximab, adalimumab, and certolizumab pegol? |
-Binds to membrane bound TNF-a on macrophages or activated T cells and induces cell death
-Binds to soluble TNF-a and prevents it from binding to the TNF receptor on target cells -This prevents the inflammatory effects of TNF-a in IBD Infliximab is 25%mouse, 75%human Adalimumab is 100% human Certolizumab Pegol is 100% human |
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What other TNF antagonist is available?
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etanercept. only binds to the soluble form of tnf-a, so it inhibits it's binding to receptor on cells, but has not been shown to be useful in the tx of IBD
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Biological Response Modifiers:Selective adhension-molecule inhibitor
MoA |
Natalizumab (Tysabri)
Monoclonal antibody to a4 integrin (not tnf-a) Integrins - adhesion and migration of immune cells into inflamed tissue -Binds specifically to a4-subunits of a4b1 and a4b7 integrins expressed on the surface of all leukocytes (except neutrophils) and inhibits the a4-mediated adhesion of leukocytes to their counterreceptors. -This prevents leukocyte migration from peripheral blood into the inflamed tissue |
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Biological Response Modifiers clinical use
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Moderate to severe Crohn’s disease
-Induce remission -Maintain remission Fistulizing Crohn’s disease Moderate to severe ulcerative colitis (infliximab) -Induce remission -Maintain remission Adalimumab can be used in patients who have lost response to, or are intolerant to infliximab (100% vs 75% human) |
