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GI > IBD Med Chem > Flashcards

IBD Med Chem Flashcards

1
Q

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

A

intestinal stem cells

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2
Q

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

A

goblet cells

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3
Q

What cells produce antimicrobial peptides (AMPs)?

A

paneth cells

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4
Q

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

A

Plasma cells

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5
Q

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

A

Epithelial cells
Innate immune cells

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6
Q

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

A

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

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7
Q

What anti-inflammatory regulators are formed by dendritic cells?

A

interlukin-10 and TGF-beta

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8
Q

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

A

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

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9
Q

Which cells provide rapid responses against reinfection?

A

CD4+ and CD8+

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10
Q

How does the intestinal immune system get off balance?

A
  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
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11
Q

What is microbial dysbiosis?

A
  1. disruption of the mucus layer
  2. Dysregulation of epithelial tight junctions
  3. defects in paneth cells
  4. increased bacterial exposure from increased permeability
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12
Q

What role do macrophages have in IBD?

A

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

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13
Q

What role do neutrophils have in IBD?

A

release preformed molecules stored in a variety of intracellular granules

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14
Q

How does the pathobiont interrupt mucosa in early IBD dysbiosis?

A

accumulation and penetration

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15
Q

How does the pathobiont interrupt mucosa in late IBD dysbiosis?

A
  1. expansion of proteobacteria
  2. decreased commensal bacteria
  3. loss of beneficial symbiosis
  4. chronic inflammation
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16
Q

What proinflammatory molecules produce negative effects on barrier function?

A

TNF
INF

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17
Q

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

A

CD1d
RIPK1
IL-10

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18
Q

What type of T cells mediate CD?

A

T-helper 1

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19
Q

What type of T cells mediate UC?

A

T-helper 2 pathway

20
Q

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

A

IL-22
IL-23
INF
TNF

21
Q

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

A

IL-4

22
Q

What types of responses lead to inflammation in IBD?

A

Neuronal
Endocrine
Immune

23
Q

What is the MOA of TNF (-)s ?

A

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

24
Q

Which drugs are JAK inhibitors?

A

Tofacitnib
Upadacitnib

25
Q

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

A

Ustkinumab

26
Q

What are key factors that effect drug delivery?

A

mucus
commensals
pH
solubility
release

27
Q

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

A

azo (N=N) bond

28
Q

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

A

azo (N=N) linkage

29
Q

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

A

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

30
Q

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

A
  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
31
Q

What is the purpose of pH dependent released medication?

A

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

32
Q

Which Mesalamine preparation is delayed and extended release?

A

Apriso

33
Q

How is Apriso delayed and time released?

A

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

34
Q

What are problems with immunosuppressive agents?

A

Increase risk of infection and malignancies

35
Q

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?

A

LIALDA; multimatrix mesalamine

36
Q

What do systemic corticosteroids inhibit?

A

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

37
Q

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

A

Additional double bond in the A ring

38
Q

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

A

6-thioguanine nucleotides

39
Q

What are the mechanisms of thiopurines?

A

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

40
Q

What toxicities are seen with 6-thioguanine nucleotides?

A

severely suppress bone marrow

41
Q

How does long term, low dose methotrexate treat IBD?

A

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

42
Q

What is the MOA of Cyclosporine?

A

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

43
Q

What is the main surfactant used for cyclosporine oral formulations?

A

Polyoxyl 40 hydrogenated castor oil NF (CREMOPHOR)

44
Q

What is a concern with polyoxyethylated castor oil

A

can cause allergic reactions

45
Q

What is the MOA of Tacrolimus?

A

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

GI (23 decks)

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