Pharmacology 21 - Inflammatory Bowel Disease

Question 1

What are the major forms of IBD?

Answer 1

• Ulcerative colitis
• Chrons disease
• Distinction incomplete in 10% patients (indeterminate colitis)

Question 2

Describe incidence of IBD in europe

Answer 2

• UC higher than Chrons.
• 4.6/100,000 in eastern europe compared to 3.3 in chrons
• 9.8/100,000 compared to 6.3 in chrons
• Affects children, adolescents and adults

Question 3

What are genetic risk factors for IBD?

Answer 3

• 201 loci identified

- People of white European origin are most susceptible

Question 4

What are the molecular mechanisms involved in pathogenesis of IBD?

Answer 4

• Impaired mucosal defence
• Loss of tolerance
• Diverse mechanisms
• Epithelial barrier defects

Question 5

List environmental risk factors of IBD

Answer 5

• Smoking
• Medication
• Diet
• Sleep
• Stress
• Physical activity
• Air pollition
• UV exposure (vit D)
• Microbiome
• Appendectomy
• Heavy metal

Question 6

Describe the pathway of IBD

Answer 6

• Autoimmune
• Defective interaction between mucosal immune system and gut flora (infection)
• Complex interplay between host and microbes
• Disrupted innate immunity and impaired clearance
• Pro-inflammatory compensatory responses
• Physical damage and chronic inflammation

Question 7

Compare UC and CD pathologies

Answer 7

Chrons

• Th1 mediated (IFNy, TNFa, IL-17, IL-23)
• T cell expansion with defective apoptosis
• Affects all gut layers
• Any part of GI
• Patchy
• Abscesses, fissures and fistulae (openings between organs or parts of the gut) are common
• Surgery is not always curative

UC

• Th2 mediated (IL-5 and 13)
• Limited clonal expansion, normal T cell apoptosis
• Mucosa/submucosa only affected
• Affects rectum and spreads continuously proximally
• Abcesses, fissures and fistulae are not common
• Surgery is curative

Question 8

List clinical features of IBD

Answer 8

• Diarrhoea, blood, mucus, cramping
• Skin rash
• Right iliac fossa mass/pain
• Apthous ulcers
• Anaemia, uvetits, fevers, sweats and jaudice
• Abdominal pain
• Arthritis arthralgia
• Weight loss

Question 9

List the supportive therapies for IBD

Answer 9

• Fluids
• Blood transfusion/ oral iron
• Nutritional support

Question 10

List the symptomatic treatments for active disease and prevetion of remission

Answer 10

• Glucocorticoids (eg. prednisolone)
• Aminosalicyclates (eg. mesalazine)
• Immunosuppressives (eg. azathioprine)

Question 11

List potential curative therapies

Answer 11

• Microbiome manipulation

- Biologic therapies (anti-TNAa eg. infliximab and many others)

Question 12

Describe pharmacokinetics of 5-ASA derivatives

Answer 12

• Activated by gut flora
• Mesalazine absorbed by small bowel and colon
• Olsalazine (2 linked aminosalicyclates) metabolised by colonic flora to 2 molecules of 5-ASA and absorbed in the colon, where they have their activity

Question 13

List actions of aminosalicyclates

Answer 13

• Binds to PPAR receptors and acts as a transcription modulator.
• Downregulates MAPK and NF-kappa Beta, therefore decreasing pro-inflammatory cytokines (TNF-alpha, IL1beta and IL-6)
• Down regulates COX2 and pro-inflammatory prostaglandins

Question 14

Describe use of aminosalicycleates in UC

Answer 14

• Effective at induction and maintenance of remission
• Combined oral and rectal administration probably more effective than either alone for generalised disease
• Rectal delivery better for localised disease
• Probably better than glucortocoids

Question 15

Describe use of aminosalicylates in CD

Answer 15

• Ineffective in inducing remission
• May be effective in maintenance
• However, other therapies are better

Question 16

What are glucocorticoids? Give examples

Answer 16

• Examples: Prednisolone, Fluticasone, budesonide (fewer side effects)
• Powerful anti-inflammatory and immunosuppressive drugs (downregulate IL-1beta and TNF-alpha, downregulate macrophages and T cell actions)
• Derived from the hormone cortisol
• Activate intracellular Glucocorticoid Receptors which can then act as positive or negative transcription factors

Question 17

Describe use of glucocorticoids in UC

Answer 17

• Use in decline (cause lots of unwanted side effects)
• Aminosalicylates are superior
• Glucocorticoids best avoided

Question 18

Describe use of glucocorticoids in chrons

Answer 18

• Drugs of choice for inducing remission
• Budesonide preferred if mild, as less likely to get side effects compared with prednisolone. However, prednisolone is more effective.
• Likely to get side effects if used to maintain remission

Question 19

What is azothioprine?

Answer 19

• A pro-drug activated by gut flora to 6-mercaptopurine
• Can now give 6-mercaptopurine directly
• Purine antagonist
• Interferes with DNA synthesis and cell cycle replication
• Further metabolised to cause its desired effects (6-MeMPN and 6-TGN)
• Immunosuppressive

Question 20

List the effects of azathiprine on immune responses

Answer 20

Impairs

• Cell and antibody mediated immune responses
• Lymphocyte proliferation
• Mononuclear cell infiltration
• Synthesis of antibodies

Enhances T cell apoptosis

Question 21

Describe use of azathioprine in Chrons

Answer 21

• Not recommended for active disease
• Recommended for inducing remission unless in combination in Chrons
• Interferes with purine biosynthesis
• Mainly used to maintain remission
• Glucocorticoid-sparing
• Slow onset – 3 to 4 months treatment for clinical benefit
• If ineffective, biological therapes are used

Question 22

List unwanted effects of asathioprine

Answer 22

• Pancreatits
• Bone marrow suppression (caused by 6-TGN)
• Hepatotoxicity (6-MeMP)
• Increased risk of lymphoma and skin cancer (4 fold)

10% patients stop treatment because of side effects

Question 23

How can unwanted effects of GCs be minimised?

Answer 23

• Administer topically - fluid or foam enemas or suppositories
• Use a low dose in combination with another drug
• Use an oral or topically administered drug with high hepatic first pass metabolism e.g.Budesonide so little escapes into the systemic circulation

Question 24

List strategies for targeted drug delivery

Answer 24

• Nanoparticles packaged in different ways
• pH dependent polymer coating system
• Pressure/ osmotic controlled coating system (use of a semipermeable membrane and push layer, pushes drug out in lower intestine)
• Prodrug based conjugates
• Time-dependent polymer coating system (swell and burst after a specific period of time)
• Combination of time and pH, to target drugs to areas of inflammation

Question 25

What is manipulation of the microbiome?

Answer 25

- Start with exclusive enteral nutrition (liquid diet, to slow resting of the mucosa and recovery of the gut flora, although it is hard to maintain and unpalatable. Used in patients who cant take glucocorticoids) - Probiotic therapies, no evidence in CD and weak evidence for maintenance of remission in UC - Fecal microbiota replacement (benefit for UC) - Antibiotic treatment (rifaximin)

Question 26

How does antibiotic treatment of IBD work?

Answer 26

- Interferes with bacterial transcription by binding to RNA polymerase - Induces and sustains remission in moderate CD (only used if complications are directly related to infection) - May be beneficial in UC - Not absorbed from the gut - May be microbiome modulator - Rifaximin reduce inflammatory mediator mRNA in experimental colitis

Question 27

How do TNF-a antibodies work in IBD?

Answer 27

- Anti- TNFa reduces activation of TNF a receptors in the gut - Reduces downstream inflammatory events - Also binds to membrane associated TNFa - Induces cytolysis of cells expressing TNFa - Promotes apoptosis of activated T cells

Question 28

Describe pharmakokinetics of anti-TNF-alpha

Answer 28

- Infliximab given intravenously. Mops up TNF alpha to prevent downstream effects - Very long half-life (9.5 days) - Most patients relapse after 8 – 12 weeks - Therefore repeat infusion every 8 weeks

Question 29

Describe effects of anti TNFa on IBD

Answer 29

- Used successfully in the treatment of CD - Only 60% patients respond within 6 weeks - Potentially curative, but many patients relapse - Successful in some patients with refractory disease and fistulae - Very good for maintaining fistula closure - Some effects seen in UC studies

Question 30

What are the problems with anti-TNFa?

Answer 30

- 50% responders lose response within 3 years - Due to production of anti-drug antibodies and increased drug clearance - 4-5 times increase in incidence of TB, and can reactivate dormant TB - Increased risk of septicaemia - Worsening heart failure - Increased risk of demyelinating disease and malignancy - Can be immunogenic

Question 31

Describe use of infliximab in IBD

Answer 31

- Early use better than last resort | - Combined with azathioprine therapy may be more effective

Question 32

List the new targets in IBD

Answer 32

- Integrins - Interleukins (IL12, IL17, IL23) - Interleukin receptors - Janus kinase (JAK) cytoplasmic cell signalling

Question 33

What is the link between azothioprines and allopurinol?

Answer 33

- Allopurinol inhibits xanthine oxidase, therefore increasing conversion of 6-MP to 6-MeMP which is hepatotoxic - Also increases myelosuppression by 6-TGN - Therefore, be careful if giving to patients on allopurinol

Question 34

Why does budesonide cause fewer unwanted systemic effects than prednisolone?

Answer 34

It is metabolised and inactivated locally