Pharmacotherapy of ibd

Pharmacotherapy of ibd

1. Pharmacotherapy of IBD 15/03/12

2. Definition Chronic, idiopathic, inflammatory intestinal conditions 2 major subtypes: Ulcerative colitis Crohn’s disease 2 minor subtypes IBDU Indeterminate colitis

3. Montreal classification of IBD Ulcerative colitis Ulcerative proctitis Left sided UC (distal UC) Extensive UC ( pancolitis ) Crohn’s Disease (acc. to location) Ileal Colonic Ileocolonic Isolated upper GI disease

4. Etiology IBD is currently considered an inappropriate immune response to the endogenous commensal microbiota within the intestines Factors involved are: Defective immune regulation Genetic mutations Exogenous factors

5. Pathogenesis

6. Genetics About 100 genetic loci have been identified e.g. NOD2 and CCR6 Many of these muatations are shared between UC and CD e.g. JAK2 & IL-23R Many loci are also associated with risk of other diseases like rheumatiod arthritis and psoriasis

7. Exogenous factors IBD may be triggered by microbes like Bacteriodes , Clostridium difficile & E.coli This is proved by presence of antibodies against them e.g. Presence of E.coli OMP2 antibodies & ASCA Body may also react against normal flora This is supported by improvement in symptoms by antibiotics Psychosocial factors(major life events, daily stress) Cause worsening of symptoms

8. Clinical features Ulcerative colitis Cardinal symptom is bloody diarrhoea With colicky abdominal pain, urgency or tenesmus 50% patients e xperience relapse at least once Crohn’s disease Abdominal pain, diarrhoea and weight loss Systemic symptoms- malaise , fever, anorexia- more common 70-80% of patients require surgery during their lifetime

9. Feature Ulcerative colitis Crohn’s disease Involvement of GIT Large bowel Any part of GIT Rectal involvement Frequent Rare Inflammation Superficial Transmural Skip areas Absent Present Ulcers If present-Superficial Deep, serpiginous Fissures & Fistulae Less comon Very common Histology Infiltration is mainly neutrophilic Presence of granulomas diagnostic; infiltration mainly lymphocytic Smoking Protective Predicts a worse course

10. Aims of Treatment

11. Drugs used in treatment 5-ASA based therapy Glucocorticoids Immunosupressants Anti- TNF α therapy Antibiotics

12. 5-Amino Salicylic Acid ( Meselamine ) based therapy First-line therapy for mild to moderate UC and Crohn’s colitis Effective in inducing remission in both UC and CD Effective in maintenance of remission in UC

13. Mechanism of action Not related to COX inhibition Its various mechanisms are : Inhibiting IL-1 and TNF- α production Inhibiting Lipo-oxygenase pathway Scavenging of free radicals Inhibiting of NF- κ B via PPAR- γ

14. Sulfasalazine Azo bond prevents absorption in stomach and small bowel Broken down in colon by bacterial azo reductase Dose: 3 - 6 g/day for active disease 2 - 4 g/day for maintenance

15. Pharmacokinetics 20 to 30% absorbed in the small intestine, which is excreted unchanged 70% reaches the colon Splits to release 5-ASA and sulfapyridine Generates 400 mg meselamine for every gram of parent compound The sulfapyridine moiety is highly lipid soluble It is completely absorbed and undergoes acetylation & glutathione conjugation

16. Adverse effects Primarily due to sulfapyridine Dose related : Headache, fatigue, nausea Allergic reactions : Rash, Steven-Johnson syndrome, hepatitis, bone marrow suppression Decrease in sperm number and motility : reversible Nephrotoxicity : Risk of interstitial nephritis, hence renal function should be monitored

17. 2 nd Generation 5-ASA compounds Higher doses of meselamine can be used with less side effects Prodrugs - Contain the same Azo bond but sulfapyridine is replaced by Another 5-ASA – Olsalazine An inert compound (4-aminobenzoyl- β - alanine )- Balsalazide

18. Asacol : Enteric-coated form of meselamine 5-ASA is liberated at pH > 7 Site of release: Terminal ileum and colon Dose: 2.4–4.8 g/ day (acute)1.6–4.8 g/ day (maintenance) Lialda : MMX (Multi-matrix) Technology Encloses 5-ASA inside a lipophilic matrix within a hydrophilic matrix It is further encapsulated by a pH-sensitive polymer which releases drug at pH > 7 Dose: 2.4–4.8 g/ day Coated drugs

19. Pentasa : Sustained release formulation of 5 – ASA. Disintegration of capsule occurs in the stomach and the microspheres then disperse throughout the entire GIT Ethylcellulose coating to allow water absorption into the small beads containing the mesalamine Water dissolves the 5-ASA, which then diffuses out of the bead into the lumen

20. Sites of release of 5-ASA formulations

21. Topical 5-ASA formulations Rowasa : Mesalamine suspended in a wax matrix suppository Effective in active proctitis Canasa Mesalamine suspended in a suspension enema Effective in distal ulcerative colitis Advantages: Superior to topical hydrocortisone with 70-90%response rates

22. Glucocorticoids Indication: Moderate to severe IBD Not effective in maintenance of remission in either Ulcerative colitis or Crohn’s disease Once remission has been induced they should be tapered very gradually over many weeks According to their response to steroids, patients can be divided into 3 classes: Steroid-responsive - 40 % Steroid-dependent - 30 – 40 % Steroid-unresponsive - 15 – 20 %

23. Antibiotics Metronidazole, Ciprofloxacin and Clarithromycin Ulcerative colitis : Antibiotics have no role except in pouchitis Crohn’s Disease : For active inflammatory, perianal and fistulizing disease: Metronidazole - 15-20 mg/kg/day in 3 divided doses OR Ciprofloxacin – 500 mg BD For preventing post-op recurrence – Metronidazole Adverse effects Metronidazole- Nausea,metallic taste, peripheral neuropathy Ciprofloxacin: Achilles tendinitis and rupture

24. Oral Prednisolone : 40- 60 mg/day for active UC not responding to 5-ASA therapy Parenteral ( i.v .) drugs: in more severe disease Hydrocortisone: 300 mg/day Methylprednisone : 40-60 mg/day Adverse effects: Weight gain, fat redistribution, hyperglycemia, cataract, Emotional changes, osteoporosis, aseptic osteonecrosis

25. Enemas: useful in patients whose disease is limited to the rectum ( proctitis ) and left colon. Hydrocortisone is available as a retention enema (100 mg/60 ml), Usual dose is one 60-ml enema per night for 2 or 3 weeks. Hydrocortisone also can be given once or twice daily as a 10% foam suspension → delivers 80 mg hydrocortisone per application Useful in patients who have difficulty retaining the enema fluid Topical steroids

26. Controlled ileal -release preparation Equally efficacious to prednisone for ileocolonic CD Topical potency 200 times that of hydrocortisone Undergoes extensive first-pass metabolism (10% oral bioavailability) hence has fewer systemic side effects Topical therapy ( e.g. enemas and suppositories) also is effective in treating colitis limited to the left side of the colon. Dose : 9 mg/day for 2 to 3 months in mild to moderate Crohn’s Disease Its role in maintenance of remission is not yet determined Budesonide

27. Immunosuppressants Thiopurine Derivatives Mercaptopurine (6-MP) Azathioprine Methotrexate Cyclosporine

28. Azathioprine & 6- Mercaptopurine Purine analogs; both are prodrugs Mechanism of action: Impair purine biosynthesis & inhibit cell proliferation Treatment of steroid-dependent and steroid- resistant disease Uses : Maintain remission in both UC and Crohn’s disease To prevent/delay recurrence of Crohn’s disease after surgical resection To treat fistulas in Crohn’s disease

29. Metabolism Active moiety Hepato - toxic

30. Differences in TPMT ( ThioPurine Methyl Tranferase ) determine the drug’s fate

31. Drug interactions Inhibition of Xanthine oxidase by allopurinol diverts metabolism towards production of 6-thioguanine analogs Augments the risk of immunosuppression Hence patients on mercaptopurine should be warned about serious interactions with medications used to treat gout and hyperuricemia If the patient is already taking allopurinol dose decreased to 25% of standard dose

32. Adverse reactions

33. Methotrexate Mechanism of action : Impaired DNA synthesis due to Dihydrofolate reductase inhibition Decreased IL-1 production Use : Induce & maintain remission in Crohn’s disease Response is rapid han that seen with thiopurines Dose : given by i.m . or s.c . route For induction: 25mg/week To maintenance: 15 mg/week

34. Adverse reactions GI toxicity : nausea, vomiting, diarrhoea , stomatitis Minimized by concurrent administration of folic acid 5mg once weekly Hepatotoxicity : Periodic evaluation of liver enzymes Leucopenia : Periodic evaluation of CBC Pneumonitis

35. Cyclosporine Use: Severe ulcerative colitis that has failed to respond adequately to steroids To treat fistulas in Crohn’s disease Mechanism of action : Binds to cyclophilin ; the complex then inhibits calcineurin Ultimately inhibits activation of T-cells and production of IL-2

36. Adverse reactions Hypertension, gingival hyperplasia, hypertrichosis , Paresthesias , tremors, headaches Nephrotoxicity - renal function should be monitored frequently. Seizures Opportunistic infections

37. Tacrolimus Macrolide antibiotic MOA - similar to cyclosporine. Effective in adults with steroid refractory UC and CD As compared to cyclosporine 100 times more potent. Have good oral absorption despite proximal small-bowel Crohn's involvement.

38. Biological therapy Anti- TNF α drugs: Infliximab Adalimumab Certolizumab pegol Natalizumab

39. Anti- TNF α drugs

40. Infliximab Chimeric IgG1 antibody (25% mouse, 75% human) Mechanism : Binds to membrane-bound TNF- α and causes cell lysis by antibody-dependent or cell-mediated cytotoxicity Effective in active CD patients refractory to steroids and thiopurines CD patients with refractory enterocutaneous fistulas Moderate to severe ulcerative colitis Dose: 5mg/kg i.v . infusion every 8 weeks

41. Adverse reactions Acute - fever, chills, urticaria , or even anaphylaxis. Subacute - serum sickness-like reaction. Increased incidence of respiratory infections - tuberculosis or other granulomatous infections. Contraindicated in patients with severe congestive heart failure (NYHA classes III and IV) . Possible increased incidence of non-Hodgkin's lymphoma, leukemia and new-onset psoriasis

42. Antibody formation Antibodies develop in 10% of patients Leads to increased risk of infusion reactions and loss of response Strategies to minimize the development of these antibodies - Treatment with glucocorticoids or other immunosuppressives . Increasing the dose of infliximab (10 mg/kg). Decreasing the interval between infusions.

43. Adalimumab Recombinant human monoclonal IgG1 antibody. Binds TNF- α and neutralizes its function by blocking the interaction between TNF and its cell-surface receptor. Injected subcutaneously. Less immunogenic than infliximab . Used in active CD patients refractory to steroids and thiopurines

44. Certolizumab pegol Human monoclonal antibody Fab conjugated with PEG Does not contain Fc fragment Mechanism of action: Inhibits monocyte cytokine production Inhibits mast cell degranulation Effective for induction of clinical response in patients with active inflammatory CD. Less immunogenic than infliximab Given by s.c . route once monthly

45. Natalizumab Humanized IgG4 antibody against α 4 integrin

46. Approved for induction & maintenance of remission in crohn’s disease Especially useful in patients who are refractory or intolerant to anti- TNF α therapy Adverse effects: Leads to Progressive Multifocal Leucoencephalopathy (PML) Hence its use is contraindicated with other immuno -suppressive drugs- Thiopurines & steroids

47. Supportive therapy Iron, calcium and Vitamin D supplementation given in case of deficiency Oral folate routinely given to patients receiving 5-ASA therapy Vitamin B12 serum levels measured annually in case of ileal Crohn’s

48. Anti- diarrheal agents ( Loperamide , Diphenoxylate ) & anti-cholinergic drugs ( Dicyclomine ) To reduce frequency of bowel movements To relieve rectal urgency Contraindicated in severe disease or suspected obstruction :- can predispose to toxic megacolon Bile salt binders ( Cholestyramine , Colesevalam ) Prevent bile-salt induced diarrhea in patients with ileo -colic resection

49. Nutritional therapy Patients with active Crohn’s: Respond to bowel rest and Total Parenteral Nutrition (TPN) As effective as steroids in inducing remission but not for maintenance Enteral nutrition in the form of elemental or peptide-based preparations are also as effective as glucocorticoids or TPN - not palatable. Dietary intervention has no role in ulcerative colitis

50. Prebiotics Non- digestable carbohydrates such as fructo -oligosaccharides Broken down by gut flora to short-chain fatty acids Their efficacy is unproven till date Probiotics Bacteria or yeast ingested orally as therapy Administered as a single organism or as a defined mixture

51. Mechanism of action: Production of bacteriocins Production of butyrate, necessary for colonocyte function Ability to downregulate inflammation Examples: A combination product VSL #3 prevents recurrent pouchitis E. coli Nissle - Equivalent to meselamine in maintaining remission in UC

52. IBD and Pregnancy Effect of IBD on fertility: Scarring of fallopian tubes- either due to involvement of terminal ileum or as a sequalae of pouch surgery Dyspareunia - due to perirectal and perianal abscess and fistulae Decreased sperm count- secondary to 5-ASA therapy; it is reversible

53. Effect of IBD on Pregnancy: In mild or quiescent disease, fetal outcome is nearly normal Spontaneous abortions, stillbirths, and developmental defects are increased with increased disease activity, not medications. Hence any flare-up is treated aggressively Patients should be in remission for 6 months before conceiving Most patients of CD can deliver vaginally but C-section is preferred in case of anorectal and perirectal abcess / fistulae.

54. Safety of drugs 5-ASA based therapy FDA category B drugs Oral Sulfasalazine , Meselamine , Balsalazide & Topical 5-ASA agents- Safe for use in pregnancy and breast-feeding Additional folate supplementation is given- 2mg/day

55. Glucocorticoids FDA category C drug Generally considered safe in pregnancy Indicated for patients with moderate to severe disease activity Are secreted in breast milk in minute amounts and do not have any significant effect on the nursing infant

56. Antibiotics Safest antibiotics to use for short periods of time (for few weeks)- Ampicillin and Cephalosporins Metronidazole can be used after 1 st trimester Ciprofloxacin (FDA category C drug) should be avoided Tetracyclines - Contraindicated

57. Thiopurine drugs FDA category D drugs Pose minimal risk during pregnancy Secreted in negligible amounts in breast milk; pose minimal risk to the infant Scenarios for use: If the patient cannot be weaned from the drug In case of an exacerbation which requires these drugs

58. Cyclosporine A FDA Category C drug Very limited data on its use in pregnancy Avoided unless the patient requires surgery Methotrexate Teratogenic and hence absolutely contraindicated

59. Anti- TNF α drugs FDA category B drugs Infliximab , adalimumab , certolizumab - can be used in pregnancy and lactation No increased risk of stillbirth or abortion Natalizumab - Category C drug; limited data available, hence avoided

60. Indications of surgery Ulcerative colitis Intractable/ fulminant disease Toxic megacolon Colonic obstruction/ perforation Massive colonic hemorrhage Prophylaxis of colon cancer Colonic dysplasia/ carcinoma Crohn’s Disease Small intestine Stricture/obstruction unresponsive to medical therapy Massive colonic hemorrhage Refractory fistula Colon and rectum Intractable/ fulminant disease Refractory fistula Colonic obstruction Prophylaxis of colon cancer Colonic dysplasia/ carcinoma

61. Step up therapy for Ulcerative colitis

62. Step up therapy for Crohn’s disease

63. Top down Therapy?

64. Pitfalls Safety issues : ed risk of TB, opportunistic infections, malignancies Cost factor Majority of patients have mild disease & will be overtreated

65. Drugs in the pipeline Adhesion molecule inhibitors: Vedolizumab - Anti α 4 β 7 antibody Anti MAdCAM-1 antibody Alicaforsen : anti ICAM-1 antisense oligonucleotide ; inhibits ICAM-1 production by endothelium by preventing translation of its m-RNA

66. L.lactis secreting IL-10 Non-invasive non-colonizing bacterium Genetically modified to secrete IL-10 , a potent anti-inflammatory molecule Allows delivery directly at the intestinal site and thus obviates systemic exposure Ustekinumab Anti IL-12/IL-23 antibody Inhibit cellular activation & cytokine production

67. Thank You!