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36 Cards in this Set

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TH1 in IBD
If the epithelial barrier is impaired, bacterial antigens (dark circles) can gain access to antigen-presenting cells in the lamina propria. These cells then present the antigen(s) to CD4+ lymphocytes and also secrete IL-12, thereby inducing the differentiation of TH1 cells in Crohn's disease (or type 2 helper T cells in ulcerative colitis).

The TH1 cells produce a characteristic array of lymphokines, including IFN-γ, which in turn activates macrophages. Macrophages positively regulate TH1 cells by secreting additional IL-12 and TNF-α
Pro vs anti inflammatory baacteria examples
Certain bacterial strains may be
either pro- (e.g., Bacteroides) or antiinflammatory (e.g., Lactobacillus), suggesting that manipulation of the colonic flora with antibiotics and probiotics may be of value in treatment of patients with IBD.
Sulfasalazine--Admin
Mesalamine-based therapy
/.;/.i. Consists of 5-aminosalicylic acid linked to sulfapyridine by an azo bond.
ii. The azo linkage in sulfasalazine prevents absorption in the stomachcand small intestine; the individual components are not liberated for absorption until colonic bacteria cleave the bond.
Sulfasalazine--mech of action
i. 5-ASA is now regarded as the therapeutic moiety, with little, if any, contribution by sulfapyridine.
ii. Mesalamine is a salicylate but its therapeutic effect is not related to cyclooxygenase inhibition.
iii. Potential sites of action include inhibition of the production of IL-1 and TNF-α, inhibition of the lipoxygenase pathway, scavenging of free radicals and oxidants, and inhibition of NF-κB.
Sulfasalazine--adverse effects
Sulfapyridine causes many of the side effects observed in patients taking sulfasalazine (e.g., allergic reactions including rash, fever, Stevens-Johnson syndrome, hepatitis, pneumonitis, hemolytic anemia, and bone marrow suppression)
Second generation 5-ASA compounds
these drugs preserve the therapeutic effect of 5-ASA without the side effects of sulfapyridine)
2nd generation 5-ASA--Prodrugs
i. Prodrugs contain the same azo bond as sulfasalazine but replace
the linked sulfapyridine with either another 5-ASA (olsalazine) or an inert compound (balsalazide).
ii. These compounds act at similar sites along the gastrointestinal tract as does sulfasalazine.
2nd generation 5-ASA--Coated Drugs
i. Delayed-release mesalamine is released throughout the small intestine and colon
ii. pH-sensitive mesalamine is released in the terminal ileum and colon.
2nd generation 5-ASA---Adverse Effects
Headache, dyspepsia, and skin rash
2nd generation 5-ASA--Clinical Uses
First line therapy for mild to moderate ulcerative colitis. Less effective in Crohn’s disease.
Glucocorticoids (Budesonide, hydrocortisone, and prednisone)
a. Mechanism of action w/ specific effects
i. Interact with steroid receptors in the cytoplasm of the cell, the
steroid-receptor complex moves into the cell nucleus where it influences protein synthesis
ii. Specific effects
(a) Annexins are synthesized; annexins inhibit PLA2 thus inhibiting the breakdown of phospholipids to arachidonic acid: this inhibits the synthesis of prostaglandins and leukotrienes
(b) Reduce the number of inflammatory cells
(c) Inhibit directly the release of inflammatory mediators
(d) Many other antiinflammatory effects
Budesonide--Admin
Available in an enteric-release form that is used for ileocecal Crohn's disease. It delivers adequate steroid therapy to a specific portion of the inflamed gut while minimizing systemic side effects because the drug undergoes extensive first-pass hepatic metabolism to inactive
derivatives if absorbed
Prednisone--Admin
Oral use for moderate to severe ulcerative colitis and Crohn’s Disease
Hydrocortisone--admin
available for IV administration in severe disease and as an enema if the disease is limited to the rectum and left colon
Gluccocorticoids--adverse effects
i. Glucocorticoids have effects on virtually every organ in the body.
ii. Systemic administration can cause numerous, at times serious, side effects
iii. Significant effects include
(a) Suppression of the hypothalamic-pituitary-adrenal axis
(b) Osteoporosis
(c) Increased intraocular pressure and cataracts
Gluccocorticoids--clinical response
i. Patients generally respond to steroids in one of three ways
(a) Steroid-responsive patients improve clinically within 1 to 2 weeks and remain in remission as the steroids are tapered and then discontinued.
(b) Steroid-dependent patients also respond to glucocorticoids but then experience a relapse of symptoms as the steroid dose is tapered.
(c) Steroid-unresponsive patients do not improve even with prolonged high-dose steroids.
ii. Patients who relapse frequently or do not improve may be treated with immunosuppressive agents
Immunosuppressives (azathioprine, mercaptopurine, methotrexate)
These drugs were developed initially for cancer chemotherapy or as immunosuppressive agents in organ transplants. They have been adapted for treatment of IBD. While their initial use in IBD was based on their
immunosuppressive effects, their specific mechanisms of action are unknown
Azathioprine and mercaptopurine--mech of action
a. Thiopurine antimetabolites which impair purine biosynthesis and inhibit cell proliferation.
b. Both are prodrugs: Azathioprine is converted to mercaptopurine, which is subsequently metabolized to 6-thioguanine nucleotides. The clinical response to azathioprine or mercaptopurine may take weeks to months.
Azathioprine and mercaptopurine--Adverse Effects
Adverse effects include pancreatitis and bone marrow suppression
Methotrexate--Mech of Action
The drug is used in treating cancer by inhibition of dihydrofolate reductase. In treating IBD, however, methotrexate has antiinflammatory effects which may be related to enhanced release of adenosine from injured cells
Methotrexate--Adverse Effects
i. GI-mucositis, vomiting and diarrhea
ii. Thrombocytopenia
iii. Nephrotoxicity
iv. Hepatotoxicity
The adverse effects can be prevented or managed with leucovorin or folic acid. Folic acid is cheaper and may be a better choice.
Infliximab--Mech of action
Biological
Infliximab is a chimeric monoclonal antibody combining portions of mouse and human IgG directed against TNF-α. Binds to TNF-α such that it cannot bind to its receptor.
Infliximab--Adverse Effects (2)
i. Increased risk of infection
There is an increased risk of infection. Those who develop infections should discontinue the drug until the infection is cured. Latent tuberculosis can become active. Tuberculin skin testing is
recommended before treatment with these drugs.
ii. Injection reactions
Infliximab is administered intravenously and can cause an infusion reaction manifested as fever and chills
Inflximab--Contraindications
i. Patients with an active infection, history of recurring infections, or medical conditions predisposing them to infection
ii. Patients with severe heart failure-these drugs increase mortality
Natalizumab
a. Mechanism of action
Natalizumab is a humanized monoclonal antibody directed against integrin molecules expressed on the cell surface of leukocytes. Integrins bind to vascular receptors in the gut, allowing leukocytes to migrate across the vascular endothelium. Natalizumab blocks this process inhibiting the inflammatory cascade (see figure).
Natalizumab---admin
IV
Natalizumab--Adverse Effects
i. Headache, fatigue, and infusion reactions
ii. Increased liver enzymes and bilirubin
iii. Progressive multifocal leukoencephalopathy (PML) is a rare brain infection usually seen in patients with HIV and other
immunocompromised patients. Immune suppression prevents the patient’s ability to fight the JC virus which is responsible for the infection. The risk of PML increases with the increasing number of
infusions.
Drugs altering balance of enteric bacteria
Alterations in the balance of enteric bacteria play a role in the development of inflammatory bowel disease. Antibiotics and probiotics themselves alter the balance bringing about beneficial effects.
Antibiotics - metronidazole and ciprfloxacin--use
-The pharmacology of these drugs was presented in the presentation on
-Drugs affecting GI motility.
-The drugs are effective in perianal or fistulizing Crohn’s disease and pouchitis.
Probiotics--species
Lactobacillus spp. and Saccharomyces boulardii
Probiotics--Mech of action
Several mechanisms of action have been proposed to explain how probiotics could have beneficial effects.
i. Acetic, lactic and propionic acid produced by Lactobacillus lowers intestinal pH inhibiting the growth of pathogenic bacteria such as Escherichia coli and Clostridium spp.
ii. Saccharomyces boulardii, (a yeast), inhibits the pathogenicity of bacterial toxins.
iii. The presence of probiotics in the intestinal tract may physically or chemically prevent adhesion and colonization of pathogenic bacteria.
iv. They may induce or enhance immune responses.
Probiotics--Adverse Effects
i. Mild gastrointestinal effects (e.g., flatulence and bloating)
ii. Infectious complications in highly immunosuppressed and/or
critically ill patients
Probiotics--Drug interactions
i. Antibiotics can inactivate bacteria-derived probiotics.
ii. Antifungals may inactivate S. boulardii
Probiotics--Efficacy
i. Probiotics are as effective as mesalamine in maintaining remission in patients with ulcerative colitis.
ii. Probiotics are less effective in maintenance of Crohn’s disease.
UC--drug therapy summary
1. Acute exacerbations of ulcerative colitis are treated with colonic-release preparations of 5-ASA and, in most patients with significant inflammation, with glucocorticoids. For milder cases involving only the rectum, these drugs may be given topically (by enema).
2. Maintenance therapy for patients with ulcerative colitis is principally in the form of 5-ASA compounds, which generally are effective and safe.
3. In patients who relapse on these preparations, purine metabolites (e.g., azathioprine-mercaptopurine) may be used.
4. Antibiotics are used for treating pouchitis while probiotics are used for maintenance of remission.
Crohn's--drug therapy summary
1. Drugs used in mild-to-moderately active Crohn's disease include sulfasalazine, budesonide, and oral corticosteroids. Oral corticosteroids and immunosuppressive agents are use for moderate to severe disease. Antibiotics are used for perianal and fistulizing disease.
2. Immunosuppressive agents (azathioprine-mercaptopurine or methotrexate) are used for maintenance of remission.
3. Infliximab and other biologicals are useful in closing fistulas in patients with Crohn's disease but can be used in acute flares of Crohn’s disease.
4. Because of the risk of serious hepatic toxicity and progressive multifocal leukoencephalopathy, natalizumab should be used only in patients who have not responded to other drugs, including a TNF inhibitor.