Drugs Used For IBD

Question 1

What are the Anti-Inflammatory Drugs

Answer 1

Sulfasalazine (5-ASA and SPD)
Glucocorticoids (Prednisolone)

Question 2

What is the MOA of Sulfasalazine (5-ASA and SPD)

Answer 2

5-ASA and SPD are bonded tightly by an azo bond. This holds the components together until it reaches the colon, where it is broken down by colonic bacteria.

Azo bond broken in the colon → 5 ASA stay in the colon and has antiinflammatory effect → SPD enters the bloodstream and has immunomodulatory effects

Question 3

What Effect does Sulfasalazine (5-ASA and SPD) do?

Answer 3

Inhibit production of IL-1 and TNF-alpha

Inhibit lipoxygenase pathway

Inhibit PPAR-gamma and NF-kB (transcription factor in production of inflamm mediators)

SPD is used in RA due to its immunomodulatory effect

Question 4

What are the Therapeutic uses of Sulfasalazine (5-ASA and SPD)

Answer 4

Maintenance in mild to moderate ulcerative colitis
Used together with GC for severe UC

Question 5

AE of Sulfasalazine (5-ASA and SPD)

Answer 5

Rashes, Steven Johnson syndrome, nephrotoxicity

Sulfa drugs are commonly associated
with allergic reactions and nephrotoxicity

Question 6

MOA of Prednisolone

Answer 6

GC bind to transcortin → the complex is released into the cytoplasm → binds to GC receptors and activates it → HSP-70 and IP (proteins) are removed → the activated complex receptor now goes to the nucleus → act on GC responsive element (GRE) → transcription occurs → synthesis of mRNA → mRNA move back into cytoplasm and synthesis proteins → proteins inhibit phospholipase A2

(Transcortin functions to transport steroid hormones (especially cortisol) in the blood.)

Question 7

What Effect does Prednisolone do?

Answer 7

Produce proteins that inhibit phospholipase A2

Reduce phagocytosis of macrophages

Reduce leukocyte localization on endothelial cells

Reduce T and B cell activation

Reduce fibroblast proliferation

Question 8

Clinical Use of Prednisolone

Answer 8

Moderate to severe IBD

Prednisolone used in Crohn’s

Budesonide used in ileocecal Crohn’s

GC enemas used in disease limited to rectum and left colon

Question 9

AE of Prednisolone

Answer 9

Buffalo hump, moon face, thinning of skin, increased abdominal fat, muscle wasting, easy bruising, poor wound healing, cataract

Long term AE Peptic ulcer, edema, hypokalaemia, glaucoma, HPA axis suppression

Question 10

What are the immunosuppressive drugs

Answer 10

Thiopurine derivatives ( Azathioprine 6-mercaptopurine)
Methotrexate
Cyclosporine (anticancer drug)

Question 11

MOA of Thiopurine derivatives ( Azathioprine 6-mercaptopurine)

Answer 11

Pathways
1. Azathioprine → 6-MP →converted into 6-thioguanine by HGPRT → incorporated into DNA → DNA damage

2. Azathioprine → 6-MP → converted into 6-thiouric acid by xanthine oxidase
3. Azathioprine → 6-MP → converted into 6-methyl MP by thiopurine methyltransferase (TPMT)

As a result Impair purine biosynthesis and inhibit cell proliferation.

Question 12

Clinical Use of Thiopurine derivatives ( Azathioprine 6-mercaptopurine)

Answer 12

Used tgt with GC in UC and Crohn’s Disease

Patients with low TPMT should be given lesser dose of MP ; high TPMT should give higher dose

Question 13

AE of Thiopurine derivatives ( Azathioprine 6-mercaptopurine)

Answer 13

Nausea, vomiting, mucosal toxicity, bone marrow suppression, increased risk of infection

DDI
6-MP interacts with allopurinol. Taken together the drug will reduce XO, increasing conc. of 6-MP → bone marrow suppression

Question 14

MOA of Methotrexate

Answer 14

Irreversibly binds to dihydrofolate reductase (DHFR) and prevent conversion of folic acid to DHF and THF
Reversibly binds to thymidylate synthetase and prevent conversion of THF to purine/pyrimidine

Inhibit purine and pyrimidine synthesis
Inhibit DNA synthesis

Question 15

Clinical Use of Methotrexate

Answer 15

Only used in IBD if patient are steroid resistant or steroid dependant

Question 16

AE of Methotrexate

Answer 16

Nausea, vomiting, mucosal ulcers, hepatotoxicity, myelosuppression, megaloblastic anaemia

Question 17

DNA synthesis Pathway

Answer 17

Folic acid → DHF →
THF → purine,
pyrimidine → DNA

Question 18

MOA of Cyclosporine

Answer 18

Inhibits calcineurin
therefore Potent immunomodulator

Question 19

Clinical Use

Answer 19

Only used when other therapy fail
Used after organ transplant

Question 20

AE of Cyclosporine

Answer 20

Renal insufficiency, peripheral neuropathy, increased susceptibility to infections

Question 21

What are the Biological Agents

Answer 21

Infliximab (anti-TNF-alpha monoclonal Ab) Extremely expensive
Antibiotics (Metronidazole, ciprofloxacin, amoxicillin- clavulanate, piperacillin-tazobactam)

Question 22

MOA of Infliximab

Answer 22

Bind to soluble and membrane bound TNF-alpha → neutralises them

TNF-alpha is a cytokine that mediates TH1 immune response
(characteristic of Crohn’s disease)

Question 23

Clinica Use of Infliximab

Answer 23

Moderate to severe Crohn’s and UC

Question 24

AE of Infliximab

Answer 24

Hypersensitivity reaction, increased susceptibility to infections

Question 25

Antibiotic use for IBD

Answer 25

Used as adjunctive therapy in severe IBD, treatment of perforating/fistulizing complications of Crohn’s and as prophylaxis for recurrent Crohn’s post operation
Clavulanate is a beta lactamase inhibitor (helps antibiotic overcome bacteria resistance to penicillin)