Pharm 20 - Pharmacology of IBD

Question 1

What are the the 2 forms of IBD?

Answer 1

1. Ulcerative colitis (UC)
2. Crohns Disease (CD)

Roughly 10% have indeterminate colitis (unclear distinction)

Question 2

Obesity is a RF for which form of IBD?

Answer 2

CD, not a RF for UC

Question 3

Name 4 RFs for IBD

Answer 3

1. Genetic predisposition (163 loci)
2. Smoking
3. Diet
4. Gut microbiome

Question 4

What is the pathogenesis of the disease

Answer 4

Improper interaction between mucosal immune system and gut flora

Question 5

UC is mediated by which helper cell?

Answer 5

Th1

Question 6

CD is mediated by which helper cell?

Answer 6

Th2

Question 7

Which cytokines influence UC

Answer 7

IL-5 and IL-13

Question 8

What is the main cytokine in CD

Answer 8

TNF-a

Question 9

Which gut layers does UC affect

Answer 9

Mucosa and submucosa

Question 10

Which gut layers does Crohns affect

Answer 10

All layers

Question 11

What differences are there in pattern of inflammation of UC. vs CD

Answer 11

UC = continuous inflammation

CD = patchy inflammation

Question 12

Where does UC start and spread?

Answer 12

Starts at rectum and spreads proximally

Question 13

UC is curative why.

Answer 13

Surgery to remove affected piece of bowel and it won’t reoccur.

Question 14

Is CD curative

Answer 14

No, as it may reoccur.

CD more likely to get abscesses, fissures and fistulae

Question 15

IBD can have systemic effects?

Answer 15

Y

Question 16

What are the supportive therapies for IBD

Answer 16

1. Fluid/electrolyte replacement

2. Nutritional support

Question 17

What are the symptomatic treatments for IBD

Answer 17

1. Glucocorticoids (e.g. prednisolone)
2. Aminosalicylates (e.g. mesalazine)
3. Immunosuppressives (e.g. azathioprine)

Question 18

What are the potentially curative therapies for IBD and how do they work

Answer 18

Manipulate gut microbiome

1. Anti-TNF a (e.g. infliximab)
2. Anti-a-4-integrin (e.g. natalizumab)

Question 19

Aminosalicylates are more effective in treating which form of IBD

Answer 19

UC - first line for inducing and maintaining remission

Question 20

Give 2 examples of aminosalicylates

Answer 20

Mesalazine (aka 5-aminosalicylic acid - 5-ASA)

Olsalazine - more complex as it consists of 2 5-ASA molecules)

Question 21

What property do aminosalicylates have that makes them useful

Answer 21

Anti-inflammatory

Question 22

How are aminosalicylates anti-inflammatory?

Answer 22

They inhibit:

1. IL-1
2. TNF-a
3. Platelet activating Factor (PAF)

They also decrease antibody secretion and cell migration.

Question 23

Mesalazine does not need to be metabolised - where is it absorbed

Answer 23

In the small bowel and colon

Question 24

Olsalazine (5-ASA derivative) is only absorbed in the colon. Why

Answer 24

It is a more complicated drug and must be activated by colonic flora

Question 25

Combined therapy of topic 5-ASA and oral what is ideal for inducing remission of UC?

Answer 25

Oral steroids. (though topical 5-ASA better than topical steroids alone)

Question 26

Which are better for treating UC; aminosalicylates or glucocorticoids?

Answer 26

Aminosalicylates Though glucocorticoids can be used topically/IV if severe

Question 27

What are the drugs of choice for inducing remission in Crohns disease?

Answer 27

Glucocorticoids (side effects possible)

Question 28

Name 2 properties of glucocorticoids (e.g. prednisone, fluticasone, budesonide)

Answer 28

1. Anti-inflammatory | 2. Immunosuppressive

Question 29

What receptors do glucocorticoids act on?

Answer 29

Intracellular glucocorticoid receptors

Question 30

3 strategies for minimising side effects of glucocorticoids

Answer 30

1. Topical administration 2. Low dose in combination with another drug 3. Use topically administered drug w high hepatic first pass metabolism (e.g. Budesonide)

Question 31

Budesonide has fewer side effects than which glucocorticoid

Answer 31

Prednisolone

Question 32

Which immunosuppressive agent has shown success in both UC and CD

Answer 32

Azathioprine

Question 33

Name 2 immunosuppressive agents aside from azathioprine

Answer 33

1. Methotrexate | 2. Cyclosporin - useful only in severe UC

Question 34

Describe azathioprine and when it is used

Answer 34

1. Immunosuppressive 2. Used to maintain remission in CD- better than placebo and budoneside 3. "Steroid-sparing" 4. Has slow onset - 3/4 months required before seeing effects

Question 35

How does azathioprine have its immunosuppressive effects

Answer 35

Azathioprine = prodrug activated in vivo by gut flora to 6-mercaptopurine - purine antagonist - interferes w/ DNA synthesis and cell replication

Question 36

What does azathioprine impair

Answer 36

1. Cell/antibody mediated immune responses 2. Lymphocyte proliferation 3. Mononuclear cell infiltration 4. Antibody synthesis

Question 37

What does azathioprine enhance

Answer 37

T cell apoptosis

Question 38

Name 4 side effects of azathioprine

Answer 38

1. Pancreatitis 2. Bone marrow suppression 3. Hepatotoxicity 4. Increased risk of lymphoma and skin cancer

Question 39

Which is the most ideal metabolism pathway for azathioprine?

Answer 39

XO pathway (xanthine oxidase pathway) - inert metabolites produced This is also the main pathway

Question 40

What cant you coadminister with azathioprine

Answer 40

Allopurinol - inhibitor of Xanthine oxidase, causing production of toxic metabolites Allopurinol is used to treat gout

Question 41

What is methotrexate an antagonist for?

Answer 41

Folate

Question 42

What does methotrexate have a demonstrable effect for?

Answer 42

CD

Question 43

What does methotrexate reduce synthesis of?

Answer 43

Thymidine / other purines Not used as there are many side effects

Question 44

3 ways in which the micro biome can be manipulated for UC/CD

Answer 44

1. Nutrition based therapies - no evidence in CD but evidence in UC 2. Faecal microbiota replacement therapies (FMT) - insufficient evidence 3. Antibiotic treatment - Rifaximin - interferes with bacterial transcription by binding to RNA polymerase (good for moderate CD and potentially UC)

Question 45

Which 2 anti-TNF-a antibodies are used for IBD (mainly CD)

Answer 45

1. Infliximab (IV) 2. Adalimumab (SC) (these are potentially curative for CD)

Question 46

Why are anti-TNF-a antibodies not as effective for UC

Answer 46

UC = th2 mediated TNF-a is a th1 cytokine

Question 47

Describe how anti-TNF-a antibodies work

Answer 47

1. Reduce activation of TNF-a receptors in the gut, also binds to membrane associated TNF-a 2. Downregulating TNF-a down regulates other cytokines (as TNF-a top of inflammatory cascade) 3. Reduced infiltration and activation of leukocytes 4. CYTOLYSIS of cells expressing TNF-a 5. APOPTOSIS of activated T-cells

Question 48

How often is infliximab given?

Answer 48

IV injection given every 8 weeks (benefits can last unto 30 weeks after 1 infusion but patients relapse after 8-12 weeks)

Question 49

What are adverse side effects of anti-TNF-a antibodies

Answer 49

Knocking out key cytokine in inflammatory cascade 4-5x increase incidence of (/reactivating) TB and other infections (e.g. septicaemia) Also can worsen heart failure, demyelinating disease, malignancy

Question 50

Why might responders lose response with anti-TNF-a antibodies?

Answer 50

The body develops anti-drug antibodies and increases drug clearance

Question 51

Name 3 potential targets for biological therapies

Answer 51

1. Alpha-4-integrin (cell adhesion molecule) 2. IL-13 - particularly UC 3. Janus kinases 1,2,3 - block signalling by il-2,4,9,15,21 (useful in UC)