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Flashcards in IBD Pharm Deck (51):
1

What are the major subtypes of inflammatory bowel disease (IBD)?

Crohn's Disease

Ulcerative colitis

2

Briefly describe the role of the balance between bowel bacteria and defensive factors in the development of IBD.

Dysbalance can occur in a diseased colon from:

1) bowel flora becomes more aggressive

2) defensive factors (mucus, antimicrobial molecules, epithelium) decrease due to impacts from environmental factors or genetic predisposition

3

What parts of GIT does Crohn's disease affect?

Entire GIT, although discontinuously

Inflammation of entire wall can pass through segments, affects regional lymph nodes

4

What areas of GIT does ulcerative colitis affect?

Always starts and rectum and moves up to colon

Neutrophil dominated inflammation of mucosa

5

What complications are associated with Crohn's disease?

Abscesses

Fistulas

Stenosis

Colon cancer

6

What complications are associated with ulcerative colitis?

Bleeding

Toxic megacolon

Colon cancer

7

What is the MOA for mesalamine (5-ASA)?

Inhibits prostaglandin production

May inhibit NFkB activity

8

List the clinical uses for 5-ASA

✅Mild to moderate ulcerative colitis (1st line Tx)
For induction + maintenance of remission

🎨Off-label for Crohn's disease

9

Describe the role of the azobond and the bowel bacteria in the delivery of 5-ASA to its site of action in the distal GIT.

The azo bond was incorporated into the structure of 5-ASA based therapy in order to deliver the drug to the distal GI tract (distal small bowel or colon).

Only bacteria in the bowel can digest the azo structure - this decreases absorption of the drug in the small intestine.

10

What are important examples of 5-ASA based therapy?

Sulfasalazine

Balsalzide, Olsalazine

Pentasa

Asacol

Rowasa

Canasa

11

What are the adverse effects of sulfasalazine?

(From systemic effects of sulfapyridine)

Pruritis, rash

GI: abdominal pain, loss of appetite, N/V

IMPAIRS FOLATE ABSORPTION => DIETARY SUPPLEMENTATION WITH FOLIC ACID recommended

12

What are adverse effects of olsalazine and balsalazide?

Secretory diarrhea

13

What segment of GI tract do sulfasalazine and balsalazide?

Colon

14

What segments of GI tract does Pentasa release 5-ASA?

All 5 -

Jejunum

Ileum

Colon = proximal, distal

Rectum

15

What region of GIT does Asacol release 5-ASA to?

Ileum

Colon

Rectum

16

What region of GI tract does Rowasa release 5-ASA?

It's an enema = (distal colon and rectum)

17

What region of GIT does Canasa release 5-ASA?

Rectum - it's a suppository

18

What are examples of glucocorticoids?

Prednisone

Budesonide

Hydrocortisone

19

What's the MOA of glucocorticoids?

Inhibit PLA2, leading to decreased synthesis of prostaglandins and leukotrienes

This in turn leads to suppressed gene transcription of NOS, COX2 and NFkB = decreased production of inflammatory cytokines and chemokines

20

What is the clinical use of glucocorticoids?

Moderate to severe ACTIVE IBD

⏰For acute exacerbation, not for long term!

21

What are side effects of glucocorticoids?

🌝Moon face

🍭Hyperglycemia (breaks down proteins to get AA's to stimulate gluconeogenesis and end up with inc. glucose)

💧Na/fluid retention
Thin extremities
Abdominal/ back of shoulders fat deposits
Inc. susceptibility to infection (since dec. inflam. Response)
💢Osteoporosis

Thin skin, purple striae, bruises

22

What are examples of immunosuppressive agents?

Thiopurine derivatives

Methotrexate

23

What are examples of Thiopurine derivatives?

What is special about both forms?

Mercaptopurine (6-MP)

Azathioprine

BOTH ARE PRODRUGS

24

What is the MOA of thiopurine derivatives?

Incorporation of false nucleotides into DNA leads to strand breakage. This inhibits proliferation of the inflammatory cells (since fast proliferating cells are most affected, including skin, GI, bone marrow cells as well)

25

What are 3 enzymes responsible for metabolism of 6-MP?

thiopurine methyltransferase (TPMT)

hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

xanthine oxidase (XO)

26

Diagram the metabolism of 6-MP into active and inactive metabolic products including the three enzymes responsible.

6-MP is metabolized by 3 enzymes

1) TPMT will methylated it to turn it into an inactive moiety

2) XO will metabolize it into 6-thiouric acid (an inactive moiety)

3) HGPRT will break it down into acid that then becomes 6-thioguanine nucleotides, the ACTIVE moiety

27

What is the clinical use of thiopurine derivatives?

🔃Maintenance of remission in ulcerative colitis and Crohn's disease

28

What are adverse effects of thiopurine derivatives?

Hematologic: bone marrow suppression

👴🏼Dermatologic: alopecia, rash

GI: N/V

Hepatotoxicity

⚠️Hypersensitivity reactions

🚧Inc. risk of infections and malignancies (black box)

29

Describe the consequences of variations in TPMT activities in the population on the effects of thiopurine derivatives.

TPMT levels low or absent in some of the population

This leads to increased risk of BM depression

TMPT levels need to be measured before therapy!

30

What are DDIs with thiopurine derivatives?

Allopurinol

It inhibits XO, which would lead to increased synthesis of the active moiety, resulting in severe leukopenia

31

How does methotrexate relate to folic acid?

Folic acid is needed for DNA synthesis

Methotrexate (MTX) is a folic acid antagonist

32

What is the MOA of MTX?

Competitive inhibitor of dihydrofolate reductase leads to impaired DNA synthesis

33

What is the clinical use of MTX?

🔃Maintenance of remission in ulcerative colitis and Crohn's disease

34

What are adverse effects associated with MTX?

👴🏼☀️Dermatologic: alopecia, photosensitivity, rash

GI: diarrhea, N/V, hepatotoxicity

Hematologic: bone marrow suppression

35

What are DDIs associated with MTX?

Drugs that inhibit renal excretion of MTX:

Salicylate
NSAIDs
Penicillin

36

What are contraindications for MTX?

Pregnancy (need folic acid!)

Hepatic disease

37

What are examples of anti-TNF therapy?

Infliximab

Adalimumab

Certulizumab pegol

Golimumab

38

What is TNF?

Key pro-inflammatory cytokine in IBD

Produced by variety of immune cells. Its binding to the TNF receptor leads to NFkB activation, resulting in pro-inflammatory cytokine production, T cell activation, proliferation and apoptosis

39

What is the MOA of anti-TNF therapy?

All 4 antibodies bind to soluble and membrane bound TNF, which prevent TNF from binding to its receptors

40

What is the clinical use of anti-TNF therapy?

Induce and maintain remission in Crohn's disease and UC

Infliximab, adalimumab, golimumab = UC
Infliximab, adalimumab, certulizumab = CD

Drug of choice for fistulizing Crohn's disease

41

What are adverse effects associated with anti-TNF therapy?

👾Increased infections (since it dampens the inflammatory response) => all patients must undergo TB test!

⚔️Antibodies can develop to the antibody Tx - particularly with Infliximab since it has a mouse antigen-binding domain

Acute adverse infusion reaction: fever, headache, dizziness, urticaria, hypotension, SOB, muscle spasms, chest discomfort

Severe hepatic reactions (rare)

Inc. lymphoma risk

42

What are examples of anti-integrin therapy?

Natalizumab

Vedolizumab

43

What are integrins?

Adhesion molecules that allow white blood cells to extravasated to sites of inflammation

44

What is the MOA of natalizumab?

Forms antibody against VLA-4, resulting in reduced extravasation of lymphocytes

45

What is the clinical use of Natalizumab?

🔃Maintenance of remission of Crohn's disease

46

What are adverse effects of Natalizumab?

Progression multifocal leukoencephalopathy (from reactivation of JC virus in brain)

Hepatotoxicity

47

What is the MOA of vedolizumab?

Antibody formed against integrin, resulting in reduced extravasation of lymphocytes into GI

48

What is the clinical use of vedolizumab?

✅🔃Induction and maintenance of remission of Crohn's disease and ulcerative colitis

49

What are adverse effects of vedolizumab?

Similar to natalizumab:

Progressive multifocal leukoencephalopathy

Hepatotoxicity

50

What agents can be used to induce remission of ulcerative colitis?

5-ASA

Glucocorticoids

Vedolizumab

Anti-TNF therapy (infliximab, adaliumab, golimumab)

51

What agents can be used for induction of remission for Crohn's disease?

Glucocorticoids

Anti-TNF

Anti-Integrin = Vedolizumab