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Flashcards in Pharm 20 - Pharmacology of IBD Deck (51)
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1
Q

What are the the 2 forms of IBD?

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

Roughly 10% have indeterminate colitis (unclear distinction)

2
Q

Obesity is a RF for which form of IBD?

A

CD, not a RF for UC

3
Q

Name 4 RFs for IBD

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

What is the pathogenesis of the disease

A

Improper interaction between mucosal immune system and gut flora

5
Q

UC is mediated by which helper cell?

A

Th1

6
Q

CD is mediated by which helper cell?

A

Th2

7
Q

Which cytokines influence UC

A

IL-5 and IL-13

8
Q

What is the main cytokine in CD

A

TNF-a

9
Q

Which gut layers does UC affect

A

Mucosa and submucosa

10
Q

Which gut layers does Crohns affect

A

All layers

11
Q

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

A

UC = continuous inflammation

CD = patchy inflammation

12
Q

Where does UC start and spread?

A

Starts at rectum and spreads proximally

13
Q

UC is curative why.

A

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

14
Q

Is CD curative

A

No, as it may reoccur.

CD more likely to get abscesses, fissures and fistulae

15
Q

IBD can have systemic effects?

A

Y

16
Q

What are the supportive therapies for IBD

A
  1. Fluid/electrolyte replacement

2. Nutritional support

17
Q

What are the symptomatic treatments for IBD

A
  1. Glucocorticoids (e.g. prednisolone)
  2. Aminosalicylates (e.g. mesalazine)
  3. Immunosuppressives (e.g. azathioprine)
18
Q

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

A

Manipulate gut microbiome

  1. Anti-TNF a (e.g. infliximab)
  2. Anti-a-4-integrin (e.g. natalizumab)
19
Q

Aminosalicylates are more effective in treating which form of IBD

A

UC - first line for inducing and maintaining remission

20
Q

Give 2 examples of aminosalicylates

A

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

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

21
Q

What property do aminosalicylates have that makes them useful

A

Anti-inflammatory

22
Q

How are aminosalicylates anti-inflammatory?

A

They inhibit:

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

They also decrease antibody secretion and cell migration.

23
Q

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

A

In the small bowel and colon

24
Q

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

A

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

25
Q

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

A

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

26
Q

Which are better for treating UC; aminosalicylates or glucocorticoids?

A

Aminosalicylates

Though glucocorticoids can be used topically/IV if severe

27
Q

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

A

Glucocorticoids (side effects possible)

28
Q

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

A
  1. Anti-inflammatory

2. Immunosuppressive

29
Q

What receptors do glucocorticoids act on?

A

Intracellular glucocorticoid receptors

30
Q

3 strategies for minimising side effects of glucocorticoids

A
  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)
31
Q

Budesonide has fewer side effects than which glucocorticoid

A

Prednisolone

32
Q

Which immunosuppressive agent has shown success in both UC and CD

A

Azathioprine

33
Q

Name 2 immunosuppressive agents aside from azathioprine

A
  1. Methotrexate

2. Cyclosporin - useful only in severe UC

34
Q

Describe azathioprine and when it is used

A
  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
35
Q

How does azathioprine have its immunosuppressive effects

A

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

36
Q

What does azathioprine impair

A
  1. Cell/antibody mediated immune responses
  2. Lymphocyte proliferation
  3. Mononuclear cell infiltration
  4. Antibody synthesis
37
Q

What does azathioprine enhance

A

T cell apoptosis

38
Q

Name 4 side effects of azathioprine

A
  1. Pancreatitis
  2. Bone marrow suppression
  3. Hepatotoxicity
  4. Increased risk of lymphoma and skin cancer
39
Q

Which is the most ideal metabolism pathway for azathioprine?

A

XO pathway (xanthine oxidase pathway) - inert metabolites produced

This is also the main pathway

40
Q

What cant you coadminister with azathioprine

A

Allopurinol - inhibitor of Xanthine oxidase, causing production of toxic metabolites

Allopurinol is used to treat gout

41
Q

What is methotrexate an antagonist for?

A

Folate

42
Q

What does methotrexate have a demonstrable effect for?

A

CD

43
Q

What does methotrexate reduce synthesis of?

A

Thymidine / other purines

Not used as there are many side effects

44
Q

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

A
  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)
45
Q

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

A
  1. Infliximab (IV)
  2. Adalimumab (SC)

(these are potentially curative for CD)

46
Q

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

A

UC = th2 mediated

TNF-a is a th1 cytokine

47
Q

Describe how anti-TNF-a antibodies work

A
  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
48
Q

How often is infliximab given?

A

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

49
Q

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

A

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

50
Q

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

A

The body develops anti-drug antibodies and increases drug clearance

51
Q

Name 3 potential targets for biological therapies

A
  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)

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