INFLAMMATORY BOWEL DISEASE- CROHS DISEASE ULCERATIVE COLITIS

1. Mentor:- Presented by:-
Dr. T. Singhal Dr. Asmita Pandey

2. Introduction
• It is an idiopathic chronic disease caused by dysregulated immune response to host
microflora.
• Characterised by inflamed gut.
• Symptoms, signs and complications are determined by the extent of inflammation.
• Waxing and waning phases.
Types
• Ulcerative colitis(UC)
• Crohn’s disease(CD)
• Indeterminate colitis(IC)

4. Etiopathogenesis
Tridirectional model

5. Crohn’s Disease
Ulcerative colitis
Proposed pathogenesis of IBD and target sites for pharmacological intervention

6. Type of IBD Symptoms Signs Complications
Ulcerative colitis Gradual onset diarrhoea
with/ without blood and
mucus
Crampy abdominal pain
Urgency
Tenesmus
Fever,
malaise,
weight loss
Swollen painful joints
Pyrexia
Tachycardia
Clubbing
Anorexia
Aphthous ulcers
Tender, distended
abdomen
Severe dehydration
Heavy diarrhoea
Rectal bleed
Bowel perforation
Toxic megacolon-
enlarged bowel due to
inflammation with sepsis
Clinical Features Inflammatory Bowel Disease

7. Crohn’s disease Abdominal cramps and
pain
Persistent diarrhoea
Rectal bleeding
Sensation of incomplete
bowel evacuation
Urgency,
fever,
loss of appetite
Pyrexia
Tachycardia
Anorexia
Clubbing
Tender distended
abdomen
Anal fissures
1.Fistula- intestinal
ulcers extending upto
the wall causing fistula
to intestine, skin or
another organ.
2. Stricture- narrowing
of a section due to
scarring leads to
intestinal blockage
3. Abscess- pus
collection in abdomen,
pelvis or perianal area
4. Bowel perforation-
chronic inflammation of
intestine can cause
perforation
5. Malabsorption and
malnutrition

8. Pharmacotherapy of IBD
5 classes of drugs are useful
1. 5- aminosalicylic acid (5-ASA)
2. Corticosteroids
3. Immunomodulators
4. Biologicals
5. Antibiotics and probiotics

9. Amino salicylates
• Sulfasalazine
• Sulfapyridine+5-aminosalicylic acid- azo linkage
• Poor intestinal absorption
• Acted upon by colonic bacteria to split azo bond causes release of
5- amino salicylic acid.
• Induces remission in both UC and CD.
• Maintains remission in UC
• Dose:- 4-8g daily
Note:- Administration- with meals 0.5g BD to 1-1.5g QID
Note:- Folate supplementation and LFT and CBC to be done every 6-12 months.

10. Properties
• Blocks production of leukotrienes and prostaglandins and inhibits inflammatory
cascade
1. Active intraluminally.
2. Absorption- rapid across small bowel
3. Delayed absorption tablets are formulated by complexing with sulphapyridine.
• Sulfasalazine-
5- ASA with sulfapyridine 5-ASA
• Site of action - lower ileum ,colon
Bacterial azoreductase

11. Side effects
1. Nausea, dyspepsia, headache,
2. Impaired folate absorption, hemolytic anemia and agranulocytosis.
3. Reversible decrease in sperm count and motility- 80% males
4. Vomiting, hepatitis, agranulocytosis, pancreatitis.

12. Newer sulpha free amino salicylates
• Deliver increased amounts of pharmacologically active 5-ASA to the site of active bowel
disease, limits toxicity.
• Effective – 60-80% of UC
Mesalamine
• Absorption- rapid and complete in upper jejunum
• Inhibits COX and LOX pathways of arachidonic acid metabolism
• Lox pathway is more important in IBD and its inhibition results in reduced LTB4
• Acts as scavenger of ROS, reduce neutrophil and macrophage chemotaxis and phagocytosis
• Decrease cytokine production and immunoglobulin secretion by intestinal mononuclear cells
• Rapid renal and hepatic (acetylation) clearance
• Adverse effects- nausea, abdominal pain, watery diarrhoea and nephritis
• Dose- 1g QID with meals or 4g rectally at bedtime

13. Olsalazine
• Contains 2 molecules of ASA linked by azo bond
• Dose- 1-3g daily
Balsalazide
• Contains 1 molecule of ASA linked by an azo bond to an inert carrier
• Dose- 2.25- 6.75g daily.

15. Glucocorticoids
• Considered for active UC unresponsive to ASA therapy
• Induce 60-70% remission rate for moderate to severe CD
• No role in maintenance of IBD therapy
• Drugs are tapered after clinical remission
• Doses -
1. Prednisolone- 40-60mg daily (oral)
2. Hydrocortisone- 300mg daily (i.v.)
3. Methylprdenisolone- 40-60mg daily(oral)
4. Budesonide- 9mg daily
5. Triamcinolone

16. Hydrocortisone enemas or foams
• Used in proctitis and left sided colonic disease as an enema
• 100mg/60ml isotonic solution once or twice daily
• Patient should lie on the left side with hips elevated
• Continue for 2-4 weeks
• Then every alternate day for 1-2 weeks
• Gradual discontinuation over 1-2 week
• Treatment is continued until symptoms remit(7-28 days)
• Tapered by 2.5-5mg weekly
• Along with maintenance therapy with 5-asa or immunomodulators
• Budesonide delayed-release or enteric release formulations are used that deliver therapeutic
quantities to a specific portion of inflamed gut .
• Approved for short-term maintenance of remission (up to 3 months).
• Multimatrix formulation delays release until the local pH is greater than 7 (pH of distal
ileum), delivering the drug predominantly to the colon.

17. Comparison of sites of release of various formulations of drugs
Prodrugs contain the same azo bond as sulfasalazine but replace the linked sulfapyridine with either another 5-ASA
(olsalazine) or an inert compound (balsalazide).
Delayed-release mesalamine releases drug throughout the GI tract,
whereas pH-sensitive mesalamine is released in the small intestine and colon.

18. Immunomodulatory agents
1. 6- Mercaptopurine
2. Azathioprine
3. Methotrexate
4. Cyclosporin
5. Tacrolimus

19. Azathioprine and 6- mercaptopurine
• Used in UC and CD
• Inhibit T-cell function and may initiate T- cell apoptosis
• Used as an adjunct to GC and biologics.
• Prodrug with nonenzymatic activation into 6- mercaptopurine.
• May limit the requirement of corticosteroids and maintain remission for years.
Dose-
• Azathioprine- 2.5-3 mg/kg/po od
• 6- mercaptopurine- 1-1.5mg/kg/po od
• Require 1-3 months to produce clinical benefits, hence CSTs mustn’t be completely
withdrawn for 2 months following initiating treatment.
• Thiopurine methyltransferase(TPMT) levels must be assessed before initiating treatment.
• Other metabolites also have anti-inflammatory activity
• 4-fold increase in the risk of lymphoma in patients treated with thiopurines.

20. TPMT- Thiopurine methyltransferase
HGPRT- Hypoxanthine-guanine phosphoribosyl transferase
XO- Xanthine oxidase
Active moiety

21. Methotrexate
• Beneficial to patients with corticosteroid –refractory or dependent crohn’s disease
as well as azathioprine non responders.
• Used in combination with biologics
• Dose- 15-25 mg oral or subcutaneous weekly
• Adverse effects- nausea, vomiting, asymptomatic LFT abnormalities
• Unaltered renal clearance, thus inhibited renal excretion mechanisms lead to
toxicity
• Folate-1mg po od may relieve some side effects
• Risk factors for hepatotoxicity
• Alcohol, hepatitis B and C, obesity, diabetes, psoriasis precipitate the side effects.

22. Inflammatory bowel symptoms

23. Cyclosporin
• Cyclosporin blocks lymphocyte activation
• Documented use in CD patients with refractory fistulas and pyoderma
• Dose- 2-4mg/kg i/v continuous infusion over 24 hrs
• Erratic and incomplete absorption. TDM required
• Converted to an oral dose-6-8mg/kg od along with azathioprine or 6-mp
• >6 months therapy is contraindicated
• Adverse effects- nephrotoxicity, seizures, opportunistic infections, hypertension,
neuropathy
Tacrolimus
• Immunomodulator with similar mechanism as cyclosporin
• Better oral absorption
• Also used in patients post organ transplantation

24. Calcineurin inhibitors

25. Ozanimod
Treatment of moderate-to-severe ulcerative colitis in patients who have failed biological
therapies;
• Sphingosine-1-phosphate (S1P) receptor modulator
Metabolites inhibit MAO-B ⇒ possible hypertensive interactions with drugs that elevate
adrenergic tone, NE, and 5HT, and with dietary tyramine
• Main adverse effects are increased upper respiratory tract infections and elevated
hepatic transaminases
• Women of childbearing age should use birth control during and for 3 months after using
ozanimod

26. Non- TNFα inhibitors
Vedolizumab
Etrolizumab
Ustekinumab
Natalizumab
Exacerbation of bacterial, viral, and fungal infections can be serious with these agents, especially in presence of other
immunosuppressants. Prior to receiving antibodies to TNF, patients should be tested for TB and, if positive, receive
prophylactic TB therapy prior to administration of anti-TNF antibodies.
TNFα inhibitors
Infliximab
Adalimumab
Certolizumab pegol
Golimumab
Biologicals- anti-TNFα antibodies

27. Infliximab
• Approved for UC and CD.
• Induction and maintenance of remission in moderate to severe crohns disease or uc patients
not responding to other therapies.
• Partly humanised anti-TNFα monoclonal antibody
• Single i.v. infusion 5mg/kg over 2 hrs
• Repeat infusions at weeks 2 and 6.
• Followed by every 8th week
• To maintain remission, dose needs to be increased or interval to be shortened within a year.
• Therapeutic serum level- 6-10mcg/ml
• Patients may develop antibody against the drug.

28. Adalimumab
• Induction or maintenance of remission in moderate to severe CD
• Given with an initial loading dose of 160mg s/c and then 80 mg s/c at second week
• 40mg s/c every 2 weeks
• Therapeutic serum level- 8-12mcg/ml
• Fully humanised anti-TNFα mab
• Useful for those whom infliximab is ineffective or caused adverse effects.
Certolizumab
• 400mg s/c (2 injections of 200mg)
• Repeat at 2 and 4 weeks
• Humanised anti-TNFα mab bound to PEG(polyethylene glycol) to increase plasma t1/2
• Better in pregnant female due to less placental crossing.
Golimumab
• Approved in 2013 for UC
• Initial 200mg s/c loading dose
• Followed by 100mg at second week
• 100mg is given every 4th week

29. Non-TNF drugs
Vedolizumab
• Acts as an anti-inflammmatory by blocking α4β7 integrin
• Given as an i.v. infusion
• May cause hypersensitivity reactions.
Etrolizumab
• Humanised MAB that blocks α4β7 and αEβ7
• Given as an I.V. infusion
• Good safety profile with few serious adverse effects in trials

30. Ustekinumab
• Humanised mab against p40 subunit of IL-12 and IL-23
• Administered s/c or i/v
• No long term safety profile
Natalizumab
• Humanised mab against α-4 integrin, a adhesion molecule
• α-4 integrin is required for adhesion, transmigration and diapedesis mechanism of
WBC.
• I.V. Administration
• Discontinue after 12 weeks if no benefit of induction therapy.

31. Tofacitinib
• Approved for moderate to severe active uc not responding to other treatments.
• Janus kinase -1,3 inhibitor, inhibit TNFα
• Interferes with JAK STAT pathway, which transfers extracellular information into
the nucleus, influencing DNA transcription.
• Oral administration
• Can increase susceptibility to infections due to immunosuppression.
• Other agents- baricitinib, Upadacitinib.

32. Antibiotics- useful in cd but limited use in UC, except in toxic colitis
• Metronidazole
• Ciprofloxacin
• Rifaximin
Metronidazole
• 500-750mg po TID for 4-8weeks
• May control mid cd and heal fistulas
• Adverse effects- neurotoxicity
Ciprofloxacin
• Sometimes used with metronidazole in pediatric IBD
• 500-750mg po bd
• Fluoroquinolones exhibit neuromuscular blocking activity , to be avoided in myasthenic patients
Rifaximin
• Nonabsorbable antibiotic 200mg po TID or 800mg po bd
• May benefit active Crohn’s disease.

33. Probiotics
• Non pathogenic microbes – E. coli(Nissle strain), Lactobacillus, Saccharomyces serve as
probiotics and help prevent pouchitis.
• Effects are transient and long term colonisation is rare.
• Therapeutic infestation has been tried with Trichuris suis to stimulate t cell mediated
immunity and decrease disease activity in UC.
Fecal Transplant
• The recognition that the etiology of IBD involves dysbiosis of the intestinal microbiome
has raised interest in methods to reestablish normal microflora in patients.
• Fecal transplant involves the instillation of a preparation of feces from a healthy donor into
the colon, either by enema or during colonoscopy.
• This has proven to be an effective therapy for antibiotic-resistant C. difficile infection.
Several clinical trials have assessed the efficacy of fecal transplant in Crohn’s disease and
ulcerative colitis, with varying results

35. Supportive Therapy in IBD
• Oral iron, folate, and vitamin B12.
• Loperamide or diphenoxylate reduces the frequency of bowel movements and relieve
rectal urgency in patients with mild disease in selected circumstances.
• Cholestyramine treat bile salt–induced diarrhea.
• Anticholinergic agents reduce abdominal cramps, pain, and rectal urgency.

36. Therapy of IBD During Pregnancy
• Mesalamine and glucocorticoids are considered
safe
• Methotrexate is absolutely contraindicated.
• Pregnant patients can be maintained on
thiopurine-based immunosuppressives.
• infliximab and adalimumab, have low risk for
adverse events .
• Certolizumab pegol is safe.
• JAK inhibitors including tofacitinib are
teratogenic in animal studies.
Pediatric IBD
• Exclusive enteral nutrition is an effective
alternative
• 8 to 12 weeks of liquid formula as the source
of calories relieves symptoms and supports
growth
• Immunization status should be considered.
• Tested for latent tuberculosis, prior to
treatment with anti–tnf-α drugs.
• Live vaccines are not recommended.
• Ciprofloxacin, metronidazole, and rifaximin
can be effective in crohn’s disease.