28 Inflammatory Bowel Disease (Including Pharmacology) (2) Flashcards
1
Q
Pathogenesis of Inflammatory Bowel Disease:
Infectious and Environmental Factors (p.60)
- Non-genetic factors
- The non-genetic hypothesis is supported by the fact that:
- Support for an infectious component in the pathogenesis of IBD comes from studies that have sited:
- Specific pathogens that have been associated with IBD
- include/
- there is no proof that any one of these/
- treatment with antibiotics/
- role of normal enteric contents and bacteria in the pathogenesis of IBD.
- mucosal barrier
- normal intestinal contents and bacteria
- antibiotics and surgical procedures that divert the intestinal contents in people with IBD
A
- Non-genetic factors also play a role in the pathogenesis of ulcerative colitis and Crohn’s disease, e.g. environmental and infectious factors.
-
The non-genetic hypothesis is supported by the fact that:
- although there is a higher concordance for IBD in monozygotic twins it is not 100%
- IBD is not inherited as a simple Mendelian trait that is automatically passed from generation to generation.
-
Support for an infectious component in the pathogenesis of IBD comes from studies that have sited:
- specific pathogens associated with IBD
- the putative role of “normal” enteric bacteria present in all people.
-
Specific pathogens that have been associated with IBD
- include Mycobacterium paratuberculosis, the Measles virus, Listeria monocytogenes, and Helicobacter hepaticus.
- there is no proof that any one of these is the sole cause of IBD
- treatment with antibiotics to eliminate these pathogens does not result in resolution of IBD.
-
role of normal enteric contents and bacteria in the pathogenesis of IBD.
- a defective mucosal barrier that promotes an aberrant immune response to these luminal antigens.
- the normal intestinal contents and bacteria present in all people somehow lead to inflammation and tissue damage in patients with IBD.
- antibiotics and surgical procedures that divert the intestinal contents in people with IBD, i.e. ileostomy or colostomy, effectively control the inflammation in some cases.
2
Q
Pathogenesis of Inflammatory Bowel Disease:
Infectious and Environmental Factors:
Certain environmental factors appear to play a role in the pathogenesis of inflammatory bowel disease (p.60)
- Cigarette smoking
- Appendectomy
- Oral contraceptives
- Dietary factors
- Breastfeeding
- Hygiene
- NSAIDs
- seasonal variations
- environmental factors that are important in pathogenesis.
A
-
Cigarette smoking
- protective against ulcerative colitis
- detrimental to Crohn’s disease.
- The majority of people with ulcerative colitis are nonsmokers (never or former smokers) and many people with Crohn’s disease are smokers.
- _Appendectomy _
- protective against ulcerative colitis
- no influence on Crohn’s disease.
-
Oral contraceptives
- may influence IBD,
-
Dietary factors
- There may be an association with certain dietary factors and IBD, namely, refined sugars, fats, and fiber,
-
Breastfeeding
- protective
-
Hygiene
- a cleaner environment is associated with IBD,
- a “dirtier” environment is protective against IBD
- both Crohn’s disease and ulcerative colitis are more common in developed countries compared to underdeveloped countries and are more common in urban versus rural areas.
- _NSAIDs _
- exacerbate or trigger disease in patients with IBD.
-
seasonal variations
- relapse rates are highest in the fall and winter months.
-
environmental factors that are important in pathogenesis.
- a Western diet is a key risk factor.
- in Iran, Crohn’s disease has increased in the past 2 decades
- growing up in a household with indoor plumbing, a refrigerator, a color television and privately owned automobile where significantly associated with developing disease.
3
Q
Management of Inflammatory Bowel Disease (p.71+85)
- The goals of therapy
- Medications for IBD are divided into five main categories:
- Surgery
A
- The goals of therapy are to control symptoms and disease activity, maintain disease remission, improve quality of life, heal gastrointestinal inflammation, support nutrition and growth, prevent malignancy, and treat extraintestinal manifestations.
-
Medications for IBD are divided into five main categories:
- 5-aminosalicylates,
- corticosteroids,
- antibiotics,
- immunomodulators
- biologics.
-
Surgery
- necessary for treatment of complications of Crohn’s disease
- a cure for ulcerative colitis.
4
Q
5-Aminosalicylic Acid (5-ASA) Compounds:
Mechanism of Action (p.74)
- Sulfasalazine and the newer 5-ASA compounds/
- Sulfasalazine contains/
- Upon entering the colon/
- The sulfapyridine/
- The 5-ASA/
- Newer, better-tolerated 5-ASA preparations/
- The topical 5-ASA preparations/
A
- Sulfasalazine and the newer 5-ASA compounds are anti-inflammatory agents that interfere with the production of arachadonic acid by affecting the thromboxane and lipoxygenase synthesis pathways.
-
Sulfasalazine contains a 5-aminosalicylic acid (5-ASA) moiety that is linked to sulfapyridine by an azo bond and is delivered intact to the colon.
- Upon entering the colon, the azo bond is cleaved by bacterial azo-reductase thereby releasing sulfapyridine and 5-ASA.
- The sulfapyridine is systemically absorbed and accounts for the majority of the drug’s toxicity and intolerance.
- The 5-ASA is the active anti-inflammatory compound and is ultimately excreted in the feces.
- Newer, better-tolerated 5-ASA preparations lack the sulfapyridine moiety and are classified as agents that contain an azo-bond (balsalazide (Colazol) or are delayed (mesalamine (Asacol, Salofalk, Claversal)) or sustained-release (mesalamine (Pentasa)).
- The topical 5-ASA preparations are delivered rectally as a suppository (Canasa) or enema (Rowasa) and have minimal systemic absorption.
5
Q
5-Aminosalicylic Acid (5-ASA) Compounds
- Clinical Efficacy
- effective treatment for/
- questionable benefit for/
- play more of a role in the treatment of/
- less effective in the treatment of/
- Topical Therapy
- highly effective for the treatment of/
- The suppository preparations (5-ASA, Canasa)/
- the enema formulations (Rowasa)/
- Rectal formulations/
- The combination of oral and topical 5-ASA agents/
- Topical 5-ASA is also effective for/
- highly effective for the treatment of/
- Drug Toxicity
- Approximately 20%-30% of patients/
- The sulfapyridine moiety may also cause/
- Sulfasalazine interferes with/
- The newer 5-ASA preparations/
A
-
Clinical Efficacy
- effective treatment for mild to moderately active ulcerative colitis
- questionable benefit for the treatment of mildly Crohn’s ileocolitis.
- play more of a role in the treatment of ulcerative colitis
- less effective in the treatment of Crohn’s disease, especially moderate to severe disease.
-
Topical Therapy
-
highly effective for the treatment of mild to moderate distal ulcerative colitis and proctitis.
- The suppository preparations (5-ASA, Canasa) reach the upper rectum
- the enema formulations (Rowasa) reach the splenic flexure and distal transverse colon.
- Rectal formulations are superior to oral medications for the treatment of distal colitis and proctitis.
- The combination of oral and topical 5-ASA agents is superior to either alone.
- Topical 5-ASA is also effective for the maintenance of remission of distal colitis.
-
highly effective for the treatment of mild to moderate distal ulcerative colitis and proctitis.
-
Drug Toxicity
- Approximately 20%-30% of patients are intolerant to sulfasalazine and develop nausea, vomiting, anorexia, or headaches.
- The sulfapyridine moiety may also cause hypersensitivity reactions that include rash, fever, agranulocytosis, pancreatitis, nephritis, hepatitis, and transient male infertility due to altered spermatogenesis.
- Sulfasalazine interferes with the normal absorption of folate and treated patients should receive folic acid (1 mg/day) supplementation.
- The newer 5-ASA preparations lack the sulfa moiety and are better tolerated.
6
Q
Corticosteroids
- Mechanism of Action
- Systemic corticosteroids/
- Topical corticosteroids/
- Corticosteroids/
- Rapidly Metabolized Steroids
- The rapidly metabolized steroids/
- These “nonsystemic” steroids undergo/
- Budesonide (Entocort)/
A
-
Mechanism of Action
- Systemic corticosteroids, e.g. prednisone, hydrocortisone, prednisolone, are effective treatment for moderate to severe Crohn’s disease and ulcerative colitis but are not indicated for maintenance of remission.
- Topical corticosteroids are delivered rectally and are effective treatment for distal colitis.
- Corticosteroids are potent anti-inflammatory and immunosuppressive agents that inhibit the production of arachidonic acid, alter leukocyte function, and decrease the expression of pro-inflammatory cytokines, e.g. IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, and interferon gamma.
-
Rapidly Metabolized Steroids
- The rapidly metabolized steroids, beclomethasone dipropionate, tixocortol pivolate, fluticasone propionate, and budesonide,
- These “nonsystemic” steroids undergo extensive first pass metabolism in the liver, thereby decreasing systemic absorption and adverse events associated with traditional steroids.
- Budesonide (Entocort) is FDA approved for the treatment of Crohn’s disease: specifically, ileitis and right-sided colitis.
7
Q
Corticosteroids
- Clinical Efficacy
- effective therapy for/
- no role for/
- Topical Therapy
- administered
- effective treatment for/
- Preparations are available in the form of/
- systemic absorption
- side effects
- Drug Toxicity
- not effective for/
- Common short-term side effects
- More serious long-term side effects
- Patients who are corticosteroid dependent should be considered for/
A
-
Clinical Efficacy
- effective therapy for induction of remission for patients with moderate to severe Crohn’s disease and ulcerative colitis.
- no role for maintenance of remission.
-
Topical Therapy
- rectally administered
- effective treatment for distal colitis or as adjunctive therapy in pancolitis.
- Preparations are available in the form of suppository (hydrocortisone), foam (proctofoam), or enema (cortenema).
- have less systemic absorption than the oral formulations,
- there is still the potential for adrenal suppression and associated side effects.
-
Drug Toxicity
- not effective for maintenance of remission for ulcerative colitis or Crohn’s disease.
- Common short-term side effects include acne, moonface, striae, insomnia, fluid retention, weight gain, emotional lability, and blurred vision.
- More serious long-term side effects that may develop with repeated or sustained dosing include cataracts, osteoporosis, diabetes mellitus, and myopathy.
- Patients who are corticosteroid dependent should be considered for surgery or the addition of an immunomodulatory agent in an attempt to wean the steroid.
8
Q
Antibiotics:
Mechanism of Action
- Intestinal flora and microbial infection have been implicated as/
- Antibiotics
- may inhibit/
- prevent/
- have a role in the treatment of/
- have not been proven effective for/
A
- Intestinal flora and microbial infection have been implicated as possible triggering factors in the cascade of immuno-inflammatory events leading to inflammatory bowel disease.
-
Antibiotics
- may inhibit chemotactic peptides released by luminal bacteria
- prevent inflammation in animal models of colitis.
- have a role in the treatment of Crohn’s disease,
- have not been proven effective for ulcerative colitis (except for pouchitis that may occur in approximately 30% of patients that have undergone a total proctocolectomy and ileal pouch anal anastomosis for ulcerative colitis).
9
Q
Antibiotics
- Metronidazole (Flagyl)
- effective in treating/
- adverse effects
- Ciprofloxacin
- Rifaximin (Xifaxan)
- Drug Toxicity
- The major toxicity
- C. difficile
- will grow in the bowel when/
- associated disease has been shown to occur/
- treated with/
- detection is hampered by the fact that/
A
-
Metronidazole (Flagyl)
-
effective in treating colonic, fistulizing, and perianal Crohn’s disease.
- postoperative maintenance of Crohn’s disease.
- adverse effects include nausea, anorexia, diarrhea, dysguesia (metallic taste), peripheral neuropathy, and an antabuse reaction to alcohol.
-
effective in treating colonic, fistulizing, and perianal Crohn’s disease.
-
Ciprofloxacin
- therapeutic alternative to metronidazole
- effective in the treatment of Crohn’s ileitis.
- generally well tolerated
- should be avoided in children due to its effect on cartilage.
-
Rifaximin (Xifaxan)
- a newer antibiotic
- well-tolerated by Crohn’s patients
- works exclusively in the GI tract and does not enter the bloodstream;
- exclusively acts in the digestive tract
- often used to treat bacterial overgrowth.
-
Drug Toxicity
- The major toxicity is superinfections with Clostridium difficile (C difficile) and pseumomebranous colitis from this infection.
-
C. difficile
- will grow in the bowel when normal bacterial flora has been altered by broad spectrum antibiotics.
- associated disease has been shown to occur at higher rates in IBD patients, often resulting in hospitalizations and colectomy.
- treated with the antibitiotics metronidazole and oral vancomycin,
- detection is hampered by the fact that it mimics an IBD flare and specific stool cultures and/or toxin analysis must be performed to make the diagnosis.
10
Q
Immunomodulators:
Azathioprine (AZA) / 6-mercaptopurine (6-MP):
Mechanism of Action
- effective for the treatment for/
- Upon absorption, AZA/
- The 6-TGNs/
- These agents have/
A
- effective for the treatment for Crohn’s disease and steroid-dependent ulcerative colitis.
- Upon absorption, AZA is non-enzymatically converted to 6-MP, which is then metabolized to the active end product, 6-thioguanine nucleotide (6-TGN).
- The 6-TGNs are purine analogs that inhibit ribonucleotide synthesis and exhibit antiproliferative effects on activated lymphocytes.
- These agents have a direct anti-inflammatory effect that is probably due to suppression of T cell function and natural killer cell activity.
11
Q
Immunomodulators:
Azathioprine (AZA) / 6-mercaptopurine (6-MP)
- Clinical Efficacy
- effective in the treatment of/
- time to render a clinical response
- Immunomodulator therapy is being introduced/
- Drug Toxicity
- Side effects
- frequency
- may be/
- Idiosyncratic or allergic-type reactions
- Nonallergic-type reactions
- Azathioprine or 6-MP induced pancreatitis/
- Due to the possibility of bone marrow suppression/
- Side effects
A
-
Clinical Efficacy
- effective in the treatment of Crohn’s disease and ulcerative colitis.
- take 2-3 months to render a clinical response.
-
Immunomodulator therapy is being introduced earlier in the treatment of Crohn’s disease
- may be beneficial as first-line therapy.
-
Drug Toxicity
-
Side effects
- common and affect approximately ¼ of patients
- may be hypersensitivity reactions or dose and metabolism-dependent, nonallergic-type reactions as well as intolerance to the drug (i.e. nausea, upset stomach).
- Idiosyncratic or allergic-type reactions (dose independent) include pancreatitis, fever, rash, arthralgias, diarrhea, nausea.
- Nonallergic-type reactions (dose dependent) include bone marrow suppression, infection, or hepatitis.
- Azathioprine or 6-MP induced pancreatitis usually occurs within the first few weeks of treatment and resolves upon discontinuation of the drug.
- Due to the possibility of bone marrow suppression, routine monitoring of complete blood counts is required.
-
Side effects
12
Q
Immunomodulators:
Methotrexate
- Mechanism of Action
- Clinical Efficacy
- effective therapy for/
- has not been proven to be effective for/
- should be administered/
- may be less effective/
- onset of action and clinical response
- Drug Toxicity
A
-
Mechanism of Action
- inhibits dihydrofolate reductase and purine synthesis,
- reduces the production of IL-1, IL-2, leukotriene B4,
- may induce T cell apoptosis (programmed cell death).
-
Clinical Efficacy
- effective therapy for Crohn’s disease for induction and maintenance of remission and as a steroid sparing effect.
- has not been proven to be effective for ulcerative colitis
- should be administered parenterally (intramuscular or subcutaneous)
- may be less effective orally for the treatment of Crohn’s disease.
- Unlike 6-MP or azathioprine, methotrexate has a shorter onset of action and clinical response is usually within 4-6 weeks.
-
Drug Toxicity
- teratogenic and must not be used in pregnancy or during conception of pregnancy (both female and male patients).
- may also cause hepatotoxicity, myelosuppression, interstitial pneumonitis, oligospermia, stomatitis, and alopecia.
13
Q
Immunomodulators:
Cyclosporine
- Mechanism of Action
- Onset of Action
- Clinical Efficacy
- utilized for/
- reserved to/
- Patients who have severe ulcerative colitis may/
- benefit for patients with/
- new biologic response modifiers
- Drug Toxicity
- required to reduce the chance of toxicity
- common side effects
- Patients with a serum cholesterol level less than 120 mg/dL have an increased risk of developing/
- Patients treated with cyclosporine in combination with azathioprine or 6-MP and steroids are at increased risk of developing/
- recommended for patients treated with cyclosporine
A
-
Mechanism of Action
- lipophilic peptide that inhibits the proliferation and activation of T helper cells by interfering with IL-2 production.
- decreases recruitment of cytotoxic T cells
- inhibits production of IL-3, IL-4, tumor necrosis factor-alpha, and interferon gamma.
-
Onset of Action
- Unlike other immunomodulators, intravenous cyclosporine has an onset of action within days.
-
Clinical Efficacy
- utilized for severe hospitalized ulcerative colitis,
- reserved to a few select IBD speciality centers.
- Patients who have severe ulcerative colitis may avoid surgery and benefit from cyclosporine
- benefit for patients with severe ulcerative colitis failing steroids.
-
new biologic response modifiers (Infliximab, Adalimumab, and Certolizumab),
- little role in the treatment of Crohn’s disease
- last resort therapy for Crohn’s fistula.
-
Drug Toxicity
- significant toxicity.
- Monitoring cyclosporine blood levels is required to reduce the chance of toxicity.
- common side effects include paresthesias, hypertrichosis, tremor, hypertension, nausea, gingival hyperplasia, vomiting, headaches, nephrotoxicity, and seizures.
- Patients with a serum cholesterol level less than 120 mg/dL have an increased risk of developing seizures from cyclosporine (due to high concentrations of free or unbound drug) and should not receive this medication.
- Patients treated with cyclosporine in combination with azathioprine or 6-MP and steroids are at increased risk of developing opportunistic infections.
- prophylaxis against Pneumocystis carinii pneumonia is recommended for patients treated with cyclosporine.
14
Q
Biologics:
Anti-TNF-alpha agents Infliximab (Remicade) (p.83)
- Mechanism of Action
- Clinical Efficacy
- approved for the treatment of/
- administered/
- For patients losing response to infliximab treatment, the dose may be/
- also approved for/
A
-
Mechanism of Action
- a chimeric (human/murine) monoclonal antibody to tumor necrosis factor alpha.
- neutralizes tumor necrosis factor, one of the major cytokines elevated in Crohn’s disease
- may also cause antibody dependent cytotoxicity of activated T cells, monocytes, and macrophages.
-
Clinical Efficacy
- approved for the treatment of inflammatory and fistulizing Crohn’s disease not responding to standard therapy.
- administered as an intravenous infusion (5mg/kg) and given in an induction regimen of three separate infusions at 0,2, and 6 weeks and maintenance dosing of every 8 weeks thereafter.
- For patients losing response to infliximab treatment, the dose may be intensified by increasing to 10mg/kg or by decreasing the intervals to every 6 weeks or both.
-
also approved for
- Rheumatoid arthritis
- in patients with Crohn’s disease many of the extra-intestinal manifestations, especially arthritis, improve with anti-TNF therapy.
- refractory ulcerative colitis.
- Rheumatoid arthritis
15
Q
Biologics:
Anti-TNF-alpha agents Infliximab (Remicade):
Drug Toxicity
- tolerability
- majority of side effects
- Infusion reactions
- Delayed hypersensitivity reactions
- associated with/
- Other opportunistic infections
- recommended for patients who are receiving maintenance therapy with biologics
- may increase the rates of/
A
- generally well tolerated
- majority of side effects being mild: nausea, headaches, and upper respiratory-like illness within one week of therapy.
-
Infusion reactions
- occur in 5% of treated patients
- include symptoms of arthralgias, skin rash, nausea, shortness of breath, palpitations, and throat tightness.
-
Delayed hypersensitivity reactions
- less common
- may occur in patients who have a long delay (usually 1-2 years) between doses.
- associated with the reactivation of tuberculosis and should not be administered to patients with known active infections.
- Other opportunistic infections include histoplasmosis, coccidiomycosis and bacterial pneumonias.
- Pneumococcal vaccination is recommended for patients who are receiving maintenance therapy with biologics.
- may increase the rates of lymphoma especially when combined with other immunomodulators, e.g. azathioprine or 6 mercaptopurine.
