Pharmacology of Drugs used in Inflammatory Bowel Disease IBD

1. Drugs used
in
Inflammatory Bowel Disease (IBD)
Dr KG Bandekar
MD Pharmacology

2. IBD Forms
• Ulcerative colitis
• Crohn’s disease or Regional enteritis

3. Differences
Ulcerative colitis Crohn’s disease
Continuous without skip areas Segmental with skip areas
(skip the corn)
(C not for C…Continuous and colon)
Commonly rectum, sigmoid colon Commonly terminal ileum and/or
ascending colon
superficial, confined to mucosal layers :
Superficial inflammation
involves the entire thickness of the aff
ected segment of bowel wall :
Transmural inflammation
Fibrosis rare Fibrosis common
Malignant change may occur if > 10 yrs Malignancy rare

4. Pharmacologic Therapy
• Till date no specific therapy for these diseases.

5. Group of drugs used
A. 5 ASA (5 Aminosalicylic Acid) compounds
B. Glucocrticoids
C. Immunomodulating Drugs
i. Thiopurines (mercaptopurine and azathioprine)
ii. Methotrexate
iii. Janus kinase inhibitor (Tofacitinib)
D. Biologic Therapies
i. Anti TNF therapies ( Mnemonic… cer goli dali in)
ii. Anti integrins (Vedolizumab)
iii. Anti IL 12/23 antibody (Ustekinumab)

6. 5 ASA
• Differs from salicylic acid only by addition of
an amino group at the 5 (meta) position
• Acts topically (not systemically) in areas of
• Absorbed from the small intestine and does
not reach the distal small bowel or colon
• To prevent absorption from the proximal small
intestine, many formulations are designed to
deliver 5-ASA to distal segments of the small
bowel or the colon

7. 5 ASA preparations
A. Azo compounds
 Have Azo bond (N=N) between 5 ASA + carrier
molecule / another 5 ASA molecule
B. Mesalamine preparations
 Proprietary formulations of 5-ASA
e.g timed-release microgranules

8. A. Azo Compounds
1. Sulfasalazine = 5 ASA + sulfapyridine
2. Balsalazide = 5 ASA + 4-aminobenzoyl-P-
alanine as the carrier
3. Olsalazine = 5 ASA + 5 ASA
(***Olsalazine is probably the most reliable
preparation for delivery of 5-ASA to the colon)
….MCQ

9. Azo Compounds
• Azo bond… 5ASA not available for absorption
in small intestine
• Colon bacteria break azo bond (azoreductase
enzyme) ..… release active 5-ASA
• High concentration of 5 ASA in the terminal
ileum or colon.

10. B. Mesalamine preparations
1. Pentasa : delayed release capsules ……
5-ASA throughout the small intestine
2. Asacol : Coated with pH sensitive resin
that dissolves at pH 6–7 (distal ileum /
colon pH)
3. Apriso : -do-
4. Lialda : -do-
5. Rowasa : Enema
6. Canasa : Suppositories

11. Mesalamine preparations

12. 5 ASA : Mechanism of Action
• Local anti-inflammatory effect
• Inhibition of COX and LOX
• Inhibition of
– cytokine,
– PAF more important
– TNFa and
– Nuclear transcription factor (NFKB) generation
• Decreased PG and LT production … minor role
• No antibacterial action

13. Clinical Use : 5 ASA
• Maintaining remission in UC, while
corticosteroids are reserved to treat acute
exacerbations
• Selection of formulation depends upon site
affected…
• E.g… 5-ASA suppositories or enemas are
useful in patients with UC confined to the
rectum

14. Group of drugs used in IBD
A. 5 ASA (5 Aminosalicylic Acid) compounds
B. Glucocrticoids
C. Immunomodulating Drugs
i. Thiopurines (mercaptopurine and azathioprine)
ii. Methotrexate
iii. Janus kinase inhibitor (Tofacitinib)
D. Biologic Therapies
i. Anti TNF therapies (goli dali in)
ii. Anti integrins (Vedolizumab)
iii. Anti IL 12/23 antibody (Ustekinumab)

15. Glucocorticoids
• Short-term treatment of moderate to severe
disease
• Controlling symptoms (Not for maintenance)
• IV, oral, and topical preparations

16. Glucocorticoids : Route
• Oral
i. Prednisolone 40–60 mg/d
ii. Budesonide (pH-controlled delayed-release)
• IV
Methyl prednisolone 40- 60 mg (severe disease
with extra-intestinal manifestations and for
rapid relief)
• Topical
Hydrocortisone : enemas, foam, or suppositories

17. Mechanism of action
• Inhibit production of :
– Inflammatory cytokines (TNF A, IL -1)
– Chemokines (IL-8)
• Inhibit gene transcription of :
– Nitric oxide synthase (i NOS)
– Phospholipase A2
– COX - 2
– NF-κB
• Reduce expression of inflammatory cell adhesion
molecules

18. Group of drugs used in IBD
A. 5 ASA (5 Aminosalicylic Acid) compounds
B. Glucocrticoids
C. Immunomodulating Drugs
i. Thiopurines (mercaptopurine and azathioprine)
ii. Methotrexate
iii. Janus kinase inhibitor (Tofacitinib)
D. Biologic Therapies
i. Anti TNF therapies (Mnemonic… cer goli dali in)
ii. Anti integrins (Vedolizumab)
iii. Anti IL 12/23 antibody (Ustekinumab)

19. Mercaptopurine (MP) and
Azathioprine
• Purine antimetabolites with immunosuppressive
properties
• After absorption, azathioprine is converted by to
6-MP
• 6 MP …. Biotransformation… active 6-thioguanine
nucleotides … concentrated in cells
• Median delay of 17 weeks in onset of therapeutic
benefit after oral azathioprine or 6-MP

20. Mercaptopurine and Azathioprine
• In moderate to severe disease
• Alone or with TNF-A inhibitors
• Corticosteroid-dependent cases : May reduce
dose or stop corticosteroid use
• Use with biologic agents (especially anti-TNF
agents) : to reduce antibody formation against
the biologic agent

21. Mercaptopurine and Azathioprine
• Measurement of thiopurine methyl-
transferase (TPMT) functional activity is
recommended prior to start of thiopurine
treatment
• To be stopped in patients with absent TPMT
activity
Immune suppression

22. Azathioprine
• Only antimetabolite that is used as
immunosuppressant but not as an anticancer
drug
• Nucleotide derivative
• It is a prodrug and is activated in the body to 6-
mercaptopurine (anticancer drug).
• Major toxic effect is bone marrow suppression.
• Its dose should be reduced if allopurinol is used
concurrently because 6-MP is metabolized by
xanthine oxidase.(allopurinol inhibits xanthine
oxidase….used in gout)

23. ADR
• Risk of :
Non-Hodgkin lymphomas
Human papillomavirus (HPV)– related cervical
dysplasia
Non-melanoma skin cancer

24. Methotrexate (Mtx)
• Antimetabolite
• Orally, SC, & IM
• Inhibition of dihydrofolate reductase, an enzyme
important in the production of thymidine and
purines
• High dose : Chemotherapy … (inhibits cellular
proliferation… anti-proliferative effect)
• Low dose : No anti-proliferative effect… in IBD
– Anti-inflammatory actions
– Stimulates apoptosis and death of activated T
lymphocytes

25. Mtx
• Methotrexate has 50,000 times higher affinity
for dihydrofolate reductase than the normal
substrate DH FA. – folate antagonist
• Depresses cytokine production
• Antiinflammatory
• Use – Rheumatoid arthritis, psoriasis, IBD

26. Mtx : Use in IBD
• To induce and maintain remission in Crohn’s
disease.
• Use in UC is uncertain

27. Group of drugs used in IBD
A. 5 ASA (5 Aminosalicylic Acid) compounds
B. Glucocrticoids
C. Immunomodulating Drugs
i. Thiopurines (mercaptopurine and azathioprine)
ii. Methotrexate
iii. Janus kinase inhibitor (Tofacitinib)
D. Biologic Therapies
i. Anti TNF therapies (Mnemonic… cer goli dali in)
ii. Anti integrins (Vedolizumab)
iii. Anti IL 12/23 antibody (Ustekinumab)

28. Tofacitinib
• Second-line therapy
• Treatment of moderate to severe ulcerative
colitis (not Crohn disease) that has not
responded to anti-TNF therapy
• Oral adm
• Black box warning … risk of thrombosis
• CMDT 2022

29. Group of drugs used in IBD
A. 5 ASA (5 Aminosalicylic Acid) compounds
B. Glucocrticoids
C. Immunomodulating Drugs
i. Thiopurines (mercaptopurine and azathioprine)
ii. Methotrexate
iii. Janus kinase inhibitor (Tofacitinib)
D. Biologic Therapies
i. Anti TNF therapies (Mnemonic… cer goli dali in)
ii. Anti integrins (Vedolizumab)
iii. Anti IL 12/23 antibody (Ustekinumab)

30. Biologic Therapies
• Moderate to severe disease
• Administered early in the disease …. May
benefit

31. Anti TNF-alfa drugs
• Infliximab
• Adalimumab
• Golimumab
• Certolizumab
• Mnemonic… Cer goli dali in

32. Mechanism
• Bind and neutralize soluble & membrane-
bound TNF on macrophages and activated T
lymphocytes
• Prevent TNF stimulation of effector cells.

33. Group of drugs used in IBD
A. 5 ASA (5 Aminosalicylic Acid) compounds
B. Glucocrticoids
C. Immunomodulating Drugs
i. Thiopurines (mercaptopurine and azathioprine)
ii. Methotrexate
iii. Janus kinase inhibitor (Tofacitinib)
D. Biologic Therapies
i. Anti TNF therapies (Mnemonic… cer goli dali in)
ii. Anti integrins (Vedolizumab)
iii. Anti IL 12/23 antibody (Ustekinumab)

34. Anti-integrins
• Decrease the trafficking of circulating
leukocytes through the vasculature, reducing
chronic inflammation
• Vedolizumab

35. Anti-IL 12/23 antibody
• Ustekinumab
• Binds p40 subunit of IL-12 and IL-23,
interfering with their receptor binding on T
cells, NK cells, and antigen presenting cells

36. Thank You!