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  2. 2. Inflammatory Bowel Disease • Inflammatory bowel disease (IBD) is a spectrum of chronic, idiopathic, inflammatory intestinal conditions.
  3. 3. • Two major types of IBD: – Ulcerative colitis (UC) – Crohn's disease (CD)
  4. 4. PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE • Crohn's disease and ulcerative colitis are chronic idiopathic inflammatory disorders of the GI tract. • Although Crohn's disease and ulcerative colitis share a number of GI and extra intestinal manifestations and can respond to a similar array of drugs, emerging evidence suggests that they result from fundamentally distinct pathogenetic mechanisms
  5. 5. • Histologically, transmural lesions in CD exhibit marked infiltration of lymphocytes & macrophages, granuloma formation, & submucosal fibrosis, whereas superficial lesions in UC have lymphocytic & neutrophilic infiltrates. • The diseased bowel in CD, includes increased levels of IL-12, IFN-ϒ, & TNF- α, findings characteristic of T-helper 1 (TH1)-mediated inflammatory processes. • In contrast, the inflammatory response in UC resembles more closely that mediated by TH2 pathway
  6. 6. • Genetic analyses of CD, mutations in a gene called nucleotide-binding oligomerization domain-2 (NOD2, also called CARD15) associated with both familial & sporadic CD in Caucasians • NOD2 is expressed in monocytes, granulocytes, dendritic cells, and intestinal epithelial cells • It is proposed to function as an intracellular sensor for bacterial infection by recognizing peptidoglycans, thereby playing an important role in the natural immunity to bacterial pathogens.
  7. 7. The Inflammatory Cascade in IBD
  8. 8. DRUG THERAPY FOR IBD 5-ASA Agents • Mainstay of therapy for mild to moderate UC & CD is sulfasalazine & other 5-ASA agents. • Effective at inducing remission in both UC & CD & in maintaining remission in UC. • whether they have a role in maintaining remission in CD?
  9. 9. Mechanism of Action & Pharmacological Properties • Prototype for this class of medications is sulfasalazine, consists of 5-ASA linked to sulfapyridine by an azo bond. • Drug developed originally for rheumatoid arthritis, clinical trials demonstrated a beneficial effect on GI sym. of subjects with concomitant UC. • It is one of first example. of an oral drug delivered effectively to distal GI tract.
  10. 10. • Given individually, as 5-ASA or sulfapyridine absorbed in upper GI tract; azo linkage in sulfasalazine prevents absorption in stomach & small intestine, & individual components not liberated for absorption until colonic bacteria cleave bond.(Azo-reductases) • 5-ASA regarded as therapeutic moiety, with little, if any, contribution by sulfapyridine.
  11. 11. • Many potential sites of action demonstrated by in vitro studies for either sulfasalazine or mesalamine are: – inhibition of prod. of IL-1 & TNF-α, – inhibition of lipoxygenase pathway, – scavenging of free radicals & oxidants – inhibition of NF-kB (a transcription factor pivotal to production of infl. mediators) • Specific mechanisms of action of these drugs have not been identified.
  12. 12. • Sulfapyridine causes many of side effects in patients taking sulphasalazine. • To preserve therapeutic. effect of 5-ASA without side effects of sulfapyridine, several second- generation 5-ASA compounds have been developed. • They are divided into two groups: – Prodrugs: contain same azo bond as sulfasalazine but replace linked sulfapyridine with either another 5-ASA (olsalazine) or an inert comp.(balsalazide). – Coated drugs: delayed-release formulation or a pH- sensitive coating.
  13. 13. DOSING • Oral sulfasalazine is of proven value in pts with mild or mod. active UC, with response rates in 60-80%. • Usual dose: 4 g/day in four divided doses with food; to avoid Adverse Effects, dose increased grad. From initial dose of 500 mg BD. • Doses as high as 6 g/day can be used.
  14. 14. Oral 5-ASA Preparations PREPARATION FORMULATION DELIVERY DOSING PER DAY AZO-BOND Sulfasalazine (500mg) Sulfapyridine-5-ASA Colon 3-6 g (acute) 2-4 g (main.) Olsalazine(250mg) 5ASA-5-ASA Colon 1-3 g Balsalazide(750mg) Amionbenzoyl-alanine- ASA Colon 6.75-9 g DELAYED RELEASE Mesalamine(400,800m g) Eudragit S (pH 7) Distal ileum-colon 2.4-4.8 g(acute) 1.6-4.8 g(main.) Mesasal/Salofalk(250,5 00mg) Eudragit L (pH 6) Ileum-colon 1.5-3 g(acute) 1.5-3 g(main) SUSTAINED RELEASE Mesalamine (250, 500, 1000 mg) (Pentasa) Ethylcellulose microgranules Stomach-colon 2–4 g (acute) 1.5–4 g (main) EXTENDED RELEASE Mesalamine (0.375g) (Apriso) Ileum-colon 1.5 g (main)
  15. 15. Topical preparations • Mesalamine suspended in wax matrix suppository or in suspension enema are effective in active proctitis & distal UC. • Mesalamine enemas (4 g/60 ml) to be used at bedtime & retained for at least 8 hours & suppository (500 mg) to be used 2-3 times a day with retaining it for at least 3 hr.
  16. 16. Adverse Effects • Occur in 10-45% of pts. & related primarily to sulfa moiety. • Some are dose-related: – headache, – Nausea – fatigue, which can be minimized by giving med. with meals or by decreasing dose. • Allergic reactions: – rash, – fever, – Stevens-Johnson syndrome, – hepatitis, – pneumonitis, – hemolytic anemia – bone marrow suppression. • Also inhibits intestinal folate absorption
  17. 17. • Newer mesalamine form. are well tolerated & side effects are relatively infrequent & minor. • Headache, dyspepsia & skin rash are the most common. • Diarrhea particularly common with olsalazine • Nephrotoxicity, although rare, is a more serious concern, Mesalamine has been associated with interstitial nephritis. • Both sulfasalazine & its met. cross placenta but have not been shown to harm fetus, newer form. appear to be safe in pregnancy.
  18. 18. GLUCOCORTICOIDS • Effects of glucocorticoids on inflammatory response are numerous & well documented. • Although glucocorticoids are universally recognized as effective in acute exacerbations, their use in either UC or CD are indicated only for moderate to severe conditions.
  19. 19. • Response to steroids in individual pts. with IBD divides them into three general classes: – steroid-responsive (40%): pts. improve clinically, within 1-2 wk. & remain in remission as steroids tapered & discontinued. – steroid-dependent (30-40%): pts. also respond but then experience a relapse of symptoms as dose tapered. – steroid-unresponsive (15-20%): pts. do not improve even with prolonged high-dose. • Steroids not effective in maintaining remission in either UC or CD
  20. 20. DOSE & FORMULATIONS • Initial doses between 40-60 mg prednisone per day orally preferred; higher doses generally are no more effective. • Dose tapered over wks. to months. • Even with these slow tapers, efforts should made to minimize duration of steroid therapy. • Induce remission in majority of patients with either UC or CD. • Most pts. improved within 5 days • For more severe cases, steroids given iv, generally methylprednisolone (40-60mg/day) or hydrocortisone (300mg/d).
  21. 21. • Steroid enemas useful in pts. whose disease limited to rectum (proctitis) & left colon. – Hydrocortisone available as enema (100 mg/60 ml), & usual dose is one 60-ml enema per night for 2 or 3 weeks. • Once clinical remission induced, should be tapered according to clinical activity, normally at a rate of no more than 5 mg/wk. • Usually tapered to 20 mg/d within 4–5 weeks but often take several months to be discontinued altogether
  22. 22. SIDE EFFECTS • The side effects are : – fluid retention, – fat redistribution, – hyperglycemia, – subcapsular cataracts, – myopathy, – emotional disturbances, and – withdrawal symptoms.
  23. 23. IMMUNOSUPPRESSIVE AGENTS • Several drugs developed for cancer chemotherapy or as immunosuppressive agents in organ transplants adapted for Tt. of IBD. • Use in IBD based on immunosuppressive effects, specific mechanisms of action are unknown. • Increasing clinical experience has defined specific roles for each of these medicines as mainstays in pharmacotherapy of IBD
  24. 24. Thiopurine Derivatives • Cytotoxic thiopurine derivatives azathioprine & mercaptopurine (6MP) used to treat pts.with severe IBD or those steroid-resistant or steroid- dependent. • Thiopurine antimetabolites impair purine biosynthesis & inhibit cell proliferation. • Both are prodrugs: Azathioprine is converted to mercaptopurine, subequently. metabolized to 6-thioguanine nucleotides, presumed active moiety. • DOSE: typically azathioprine (2 to 3 mg/kg/d) or 6-MP (1.5 mg/kg/d). • Effectively maintain remission in both diseases • Immunosuppressive may be viewed as steroid-sparing agents.
  25. 25. Adverse effects • Idiosyncratic: – Pancreatitis – nausea & vomiting – Fever – Rash – arthralgias • Dose-related: – bone marrow suppression – Elevations in liver enzymes – increased risk of infection • Possible: – risk of hematological malignancies (non-Hodgkin's lymphoma)
  26. 26. Methotrexate • It inhibits dihydrofolate reductase, thereby blocking DNA synthesis & causing cell death. • Also decreases IL-1 production. • Reserved for pts. whose IBD is either steroid-resistant or steroid-dependent. • In Crohn's disease, it both induces & maintains remission, generally with a more rapid response than that seen with mercaptopurine or azathioprine. • Only limited studies examined its role in UC. • DOSE: higher doses (15-25 mg/wk) given IM/SC. • ADRs- leukopenia , hepatic fibrosis
  27. 27. Cyclosporine (CSA) • Cyclosporine (calcineurin inhibitor) effective in severe UC that failed to respond adequately to steroid therapy. • It blocks the production of IL-2 by T- helper cells. • 50-80% of severely ill pts. improve significantly (within 7 days) in response to iv (2-4 mg/kg/d). • Careful monitoring levels is necessary to maintain a therapeutic level in whole blood between 300- 400 ng/ml.
  28. 28. SIDE EFFECTS • Renal function impairment • Hypertension • Gingival hyperplasia • Tremors • Headaches • Electrolyte abnormalities • Opportunistic infections, most notably Pneumocystis carinii pneumonia.
  29. 29. ANTI-TNF THERAPY • TNF- α- key inflammatory cytokine & mediator of intestinal inflammation. • Although a great many of both pro- & anti-inflammatory cytokines generated in inflamed gut in IBD , there is some rationale for targeting TNF- α because it is one of the principal cytokines mediating TH1 immune response characteristic of CD. • Infliximab is a chimeric monoclonal Ab. against TNF- α is effective in CD. • MOA: It blocks TNF- α in serum & at cell surface & probably lyses TNF- α producing macrophages & T cells through complement fixation & antibody-dependent cytotoxicity. • Of active CD pts. refractory to steroids, 6-MP or 5-ASA, 65% respond to iv infliximab (5 mg/kg).
  30. 30. SIDE EFFECTS • Acute: – Fever – Chills – Urticaria – anaphylaxis • Subacute: – serum sickness-like • Increased incidence of resp. infections; potential reactivation of tuberculosis or other granulomatous infections with subsequent dissemination. • Possible increased incidence of non-Hodgkin's lymphoma
  31. 31. THANK YOU
  33. 33. • Is a functional bowel disorder characterized by abdominal pain or discomfort & altered bowel habits in absence of detectable structural abnormalities. • No clear diagnostic markers exist for IBS, thus diagnosis of disorder is based on clinical presentation. • IBS symptoms tend to come & go over time & often overlap with other functional disorders such as fibromyalgia, headache, backache & genitourinary symptoms.
  34. 34. Diagnostic Criteria for Irritable Bowel Syndrome Recurrent abdominal pain or discomfortat least 3 days per month in last 3 months associated with two or more of following: 1. Improvement with defecation 2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form (appearance) of stool
  35. 35. Pathophysiology • Pathogenesis of IBS is poorly understood, although roles of: – abnormal gut motor and sensory activity – central neural dysfunction – psychological disturbances – stress – luminal factors
  36. 36. • Abnormal gut motor & sensory activity: • IBS pts. may exhibit increased rectosigmoid motor activity for up to 3 h after eating. • IBS pts. frequently exhibit exaggerated sensory responses to visceral stimulation • Mech. responsible for visceral hypersensitivity are still under investigation, which may be: – increased end-organ sensitivity with recruitment of "silent" nociceptors – spinal hyperexcitability with activation of nitric oxide and possibly other neurotransmitters
  37. 37. – endogenous (cortical and brainstem) modulation of caudad nociceptive transmission – over time, possible development of long-term hyperalgesia due to development of neuroplasticity, resulting in permanent or semipermanent changes in neural responses to chronic or recurrent visceral stimulation • Central neural dysfunction: strongly suggested by clinical association of emotional disorders & stress with symptom exacerbation & therapeutic response to therapies that act on cerebral cortical sites
  38. 38. DRUG THERAPY FOR IBS Patient Counseling and Dietary Alterations • Reassurance & careful explanation of functional nature of disorder & of how to avoid obvious food precipitants are important first steps in pts. counseling & dietary change.
  39. 39. Stool-Bulking Agents • High-fiber diets & bulking agents, such as bran or hydrophilic colloid • Most gastroenterologists consider stool-bulking agents worth trying in pts. with IBS-C. • MOA: – water-holding action of fibers may contribute to increased stool bulk – speeds up colonic transit – because of their hydrophilic properties, stool-bulking agents bind water & thus prevent both excessive hydration or dehydration of stool – fiber supplementation with psyllium shown to reduce perception of rectal distention, indicating that fiber may have positive affect on visceral afferent function
  40. 40. Antispasmodics • Anticholinergic drugs may provide temporary relief for symptoms such as painful cramps related to intestinal spasm. • Most effective when prescribed in anticipation of predictable pain. • Most anticholinergics contain natural belladonna alkaloids, which may cause xerostomia, urinary hesitancy & retention, blurred vision, & drowsiness. • Synthetic anticholinergics such as dicyclomine have less effect on mucous membrane secretions & produce fewer undesirable side effects.
  41. 41. Antidiarrheal Agents • Peripherally acting opiate-based agents are initial therapy of choice for IBS-D • MOA: – increases in segmenting colonic contractions, – delays in fecal transit, – increases in anal pressures, – reductions in rectal perception • When diarrhea is severe, esp. in painless diarrhea variant of IBS, small doses of loperamide, 2–4 mg every 4–6 h up to a maximum of 12 g/d, can be prescribed • Another anti-diarrhea agent that may be used in IBS pts. Is bile acid binder cholestyramine resin.
  42. 42. Antidepressant Drugs • In addition to their mood-elevating effects, antidepressant medications have several physiologic effects • Tricyclic antidepressant (imipramine) slows jejunal migrating motor complex transit propagation & delays orocecal & whole-gut transit, indicative of a motor inhibitory effect, may alter visceral afferent neural function • Beneficial effects of tricyclic comp. in Tt. of IBS appear to be independent of their effects on depression • Therapeutic benefits for bowel symptoms occur faster & at a lower dosage • SSRI paroxetine accelerates orocecal transit, raising possibility that this drug class may be useful in IBS-C pts.
  43. 43. Antiflatulence Therapy • Pts. should be advised to eat slowly & not chew gum or drink carbonated beverages. • Probiotics • Beano, an over-the-counter oral-glycosidase sol., may reduce rectal passage of gas. • Pancreatic enzymes reduce bloating, gas, & fullness during & after high-calorie, high-fat meal ingestion
  44. 44. Serotonin Receptor Agonist and Antagonists • Serotonin rec. antagonists have been evaluated as therapies for IBS-D. • In humans, a 5-HT3rec. antagonist such as Alosetron reduces perception of painful visceral stimulation in IBS. • It is currently is approved for Tt. of women with severe IBS in whom diarrhea is predominant symptom. • Dosa: 1 mg once or twice daily, it reduces IBS-related lower abdominal pain, cramps, urgency, & diarrhea.
  45. 45. • Novel 5-HT4 rec. agonists such as Tegaserod exhibit prokinetic activity by stimulating peristalsis. • MOA: Tegaserod stimulation of 5-HT4 rec. on mucosal afferent nerve fibers triggers release of neurotransmitters from submucosal & myenteric plexuses, including calcitonin gene-related peptide, that stimulate peristaltic reflex. • These neurotransmitters stimulate proximal bowel contraction (via acetylcholine & substance P) & distal bowel relaxation (via nitric oxide & vasoactive intestinal peptide). • DOSE: 6 mg/d
  46. 46. Chloride Channel Activators • Lubiprostone is a bicyclic fatty acid that stimulates chloride channels in apical membrane of intestinal epithelial cells. • A new class of comp. for Tt. of chronic constipation with or without IBS. • Chloride secretion induces passive movement of sodium & water into bowel lumen & improves bowel function. • Major side effects are nausea & diarrhea.
  47. 47. Possible Drugs for a Dominant Symptom in IBS SYMPTOM DRUG DOSE Diarrhea Loperamide 2–4 mg when necessary/maximum 12 g/d Cholestyramine resin 4 g with meals Alosetron 0.5–1 mg bid (for severe IBS, women) Constipation Psyllium husk 3-4 g BID with meals, than adjust Methylcellulose 2 g BID with meals, than adjust Calcium polycarbophil 1 g QID Lactulose syrup 10-20 g BID 70% sorbitol 15 ml BID Polyethylene glycol 3350 17 g in 250 ml water QID Lubiprostone 24 mg BID Magnesium hydroxide 30-60 ml QID
  48. 48. Abdominal pain Smooth muscle relaxant QID Tricyclic antidepressant Start 25-50 mg HS, than adjust Selective serotonin reuptake inhibitor Begin small dose, increase as needed