IBD Med Chem

Question 1

What cells reside at the base of crypts and give rise to all absorptive and secretory cells making up the epithelial layer?

Answer 1

intestinal stem cells

Question 2

What cells produce a mucus layer that reduces exposure of intestinal epithelial cells to microbiota?

Answer 2

goblet cells

Question 3

What cells produce antimicrobial peptides (AMPs)?

Answer 3

paneth cells

Question 4

What cells produce IgA which binds mucus, preventing invasion by pathogenic organisms and helping maintain homeostatic balance between host and commensal microbiota?

Answer 4

Plasma cells

Question 5

Which 2 types of cells detect microbiota using Pattern Recognition Receptors (PRRs)?

Answer 5

Epithelial cells
Innate immune cells

Question 6

What is the normal environment of the intestinal mucosal immune system?

Answer 6

anti-inflammatory environment; active down-regulation of immune response

Question 7

What anti-inflammatory regulators are formed by dendritic cells?

Answer 7

interlukin-10 and TGF-beta

Question 8

Intestinal macrophages do not produce inflammatory cytokines, what do they do instead?

Answer 8

produce large amounts of the anti-inflammatory cytokine interleukin-10

Question 9

Which cells provide rapid responses against reinfection?

Answer 9

CD4+ and CD8+

Question 10

How does the intestinal immune system get off balance?

Answer 10

1. leaky barrier (microbial dysbiosis)
2. innate and adaptive immune cells express different profiles and numbers of molecular pattern-recognition receptors (positive feedback loop)
3. commensals are recognized as pathogens

Question 11

What is microbial dysbiosis?

Answer 11

1. disruption of the mucus layer
2. Dysregulation of epithelial tight junctions
3. defects in paneth cells
4. increased bacterial exposure from increased permeability

Question 12

What role do macrophages have in IBD?

Answer 12

Increased levels of:
TNF
IL-6
IL-23
IL-12
(proinflammatory)

Question 13

What role do neutrophils have in IBD?

Answer 13

release preformed molecules stored in a variety of intracellular granules

Question 14

How does the pathobiont interrupt mucosa in early IBD dysbiosis?

Answer 14

accumulation and penetration

Question 15

How does the pathobiont interrupt mucosa in late IBD dysbiosis?

Answer 15

1. expansion of proteobacteria
2. decreased commensal bacteria
3. loss of beneficial symbiosis
4. chronic inflammation

Question 16

What proinflammatory molecules produce negative effects on barrier function?

Answer 16

TNF
INF

Question 17

What anti-inflammatory molecules produce protective effects on barrier function?

Answer 17

CD1d
RIPK1
IL-10

Question 18

What type of T cells mediate CD?

Answer 18

T-helper 1

Question 19

What type of T cells mediate UC?

Answer 19

T-helper 2 pathway

Question 20

What cytokines are mostly involved with T-helper 1 pathway?

Answer 20

IL-22
IL-23
INF
TNF

Question 21

What cytokines are mostly involved with T-helper 2 pathway?

Answer 21

IL-4

Question 22

What types of responses lead to inflammation in IBD?

Answer 22

Neuronal
Endocrine
Immune

Question 23

What is the MOA of TNF (-)s ?

Answer 23

binds to homotrimeric TNF or soluble TNF and blocks interaction between receptor type 1 and 2; neutralizes pro-inflammatory signaling

Question 24

Which drugs are JAK inhibitors?

Answer 24

Tofacitnib
Upadacitnib

Question 25

What drug is a monoclonal antibody binds to p40 subunit and prevents actions of IL-12 and IL-23?

Answer 25

Ustkinumab

Question 26

What are key factors that effect drug delivery?

Answer 26

mucus commensals pH solubility release

Question 27

What bond is cleaved by commensal enzyme to produce 2 5-ASA or intert molecules?

Answer 27

azo (N=N) bond

Question 28

_____ ___________ prevents absorption of active drug in the upper GI tract

Answer 28

azo (N=N) linkage

Question 29

What is the purpose of ethylcellulose coated micro granules of Mesalamine?

Answer 29

time-dependent, prolonged release starting in duodenum to the rectum

Question 30

What does TNF lead to when released by macrophages and T lymphocytes?

Answer 30

1. Modulates immune cell functions 2. Drives adaptive immunity 3. Triggers epithelial apoptosis 4. Recruits immune cells (ICAM1) 5. regulates MMP expression to induce tissue degradation and damage

Question 31

What is the purpose of pH dependent released medication?

Answer 31

Dissolves at pH 6.8-7 so it reaches the terminal ileum and colon

Question 32

Which Mesalamine preparation is delayed and extended release?

Answer 32

Apriso

Question 33

How is Apriso delayed and time released?

Answer 33

Contains granules composed of Mesalamine in a polymer matrix with an enteric coating that dissolves at pH 6 and above

Question 34

What are problems with immunosuppressive agents?

Answer 34

Increase risk of infection and malignancies

Question 35

Which 5-ASA is incorporated into microparticles of a lipophilic matrix dispersed within a hydrophilic matrix then coated with a pH dependent gastric-acid resistant polymer?

Answer 35

LIALDA; multimatrix mesalamine

Question 36

What do systemic corticosteroids inhibit?

Answer 36

All parts of immune system: cytokines prostaglandins leukotrienes histamine recruitment factors adhesion

Question 37

What molecular feature of glucocorticoids make them bind with higher affinity to the glucocorticoid receptor

Answer 37

Additional double bond in the A ring

Question 38

What is the active moiety of the prodrugs azathioprine and mercaptopurine?

Answer 38

6-thioguanine nucleotides

Question 39

What are the mechanisms of thiopurines?

Answer 39

Inhibition of DNA synthesis Suppression of T cell dependent immune response Inhibition of de novo purine nucleotide biosynthesis

Question 40

What toxicities are seen with 6-thioguanine nucleotides?

Answer 40

severely suppress bone marrow

Question 41

How does long term, low dose methotrexate treat IBD?

Answer 41

leads to accumulation of adenosine, a lymphotoxic immunosuppressive and anti-inflammatory autocoid; impairs neutrophil chemotaxis

Question 42

What is the MOA of Cyclosporine?

Answer 42

binds cyclophilin and inhibits calcineurin; inhibits gene transcription of IL-2, IL-3, IFN and other factors produced by T cells

Question 43

What is the main surfactant used for cyclosporine oral formulations?

Answer 43

Polyoxyl 40 hydrogenated castor oil NF (CREMOPHOR)

Question 44

What is a concern with polyoxyethylated castor oil

Answer 44

can cause allergic reactions

Question 45

What is the MOA of Tacrolimus?

Answer 45

binds to immunophilin FK-binding protein (FKBP); inhibits calcineurin; inhibits gene transcription of IL-2, IL-3, IFN and other factors produced by T cells