IBD Med Chem Flashcards
What cells reside at the base of crypts and give rise to all absorptive and secretory cells making up the epithelial layer?
intestinal stem cells
What cells produce a mucus layer that reduces exposure of intestinal epithelial cells to microbiota?
goblet cells
What cells produce antimicrobial peptides (AMPs)?
paneth cells
What cells produce IgA which binds mucus, preventing invasion by pathogenic organisms and helping maintain homeostatic balance between host and commensal microbiota?
Plasma cells
Which 2 types of cells detect microbiota using Pattern Recognition Receptors (PRRs)?
Epithelial cells
Innate immune cells
What is the normal environment of the intestinal mucosal immune system?
anti-inflammatory environment; active down-regulation of immune response
What anti-inflammatory regulators are formed by dendritic cells?
interlukin-10 and TGF-beta
Intestinal macrophages do not produce inflammatory cytokines, what do they do instead?
produce large amounts of the anti-inflammatory cytokine interleukin-10
Which cells provide rapid responses against reinfection?
CD4+ and CD8+
How does the intestinal immune system get off balance?
- leaky barrier (microbial dysbiosis)
- innate and adaptive immune cells express different profiles and numbers of molecular pattern-recognition receptors (positive feedback loop)
- commensals are recognized as pathogens
What is microbial dysbiosis?
- disruption of the mucus layer
- Dysregulation of epithelial tight junctions
- defects in paneth cells
- increased bacterial exposure from increased permeability
What role do macrophages have in IBD?
Increased levels of:
TNF
IL-6
IL-23
IL-12
(proinflammatory)
What role do neutrophils have in IBD?
release preformed molecules stored in a variety of intracellular granules
How does the pathobiont interrupt mucosa in early IBD dysbiosis?
accumulation and penetration
How does the pathobiont interrupt mucosa in late IBD dysbiosis?
- expansion of proteobacteria
- decreased commensal bacteria
- loss of beneficial symbiosis
- chronic inflammation
What proinflammatory molecules produce negative effects on barrier function?
TNF
INF
What anti-inflammatory molecules produce protective effects on barrier function?
CD1d
RIPK1
IL-10
What type of T cells mediate CD?
T-helper 1
What type of T cells mediate UC?
T-helper 2 pathway
What cytokines are mostly involved with T-helper 1 pathway?
IL-22
IL-23
INF
TNF
What cytokines are mostly involved with T-helper 2 pathway?
IL-4
What types of responses lead to inflammation in IBD?
Neuronal
Endocrine
Immune
What is the MOA of TNF (-)s ?
binds to homotrimeric TNF or soluble TNF and blocks interaction between receptor type 1 and 2; neutralizes pro-inflammatory signaling
Which drugs are JAK inhibitors?
Tofacitnib
Upadacitnib
What drug is a monoclonal antibody binds to p40 subunit and prevents actions of IL-12 and IL-23?
Ustkinumab
What are key factors that effect drug delivery?
mucus
commensals
pH
solubility
release
What bond is cleaved by commensal enzyme to produce 2 5-ASA or intert molecules?
azo (N=N) bond
_____ ___________ prevents absorption of active drug in the upper GI tract
azo (N=N) linkage
What is the purpose of ethylcellulose coated micro granules of Mesalamine?
time-dependent, prolonged release starting in duodenum to the rectum
What does TNF lead to when released by macrophages and T lymphocytes?
- Modulates immune cell functions
- Drives adaptive immunity
- Triggers epithelial apoptosis
- Recruits immune cells (ICAM1)
- regulates MMP expression to induce tissue degradation and damage
What is the purpose of pH dependent released medication?
Dissolves at pH 6.8-7 so it reaches the terminal ileum and colon
Which Mesalamine preparation is delayed and extended release?
Apriso
How is Apriso delayed and time released?
Contains granules composed of Mesalamine in a polymer matrix with an enteric coating that dissolves at pH 6 and above
What are problems with immunosuppressive agents?
Increase risk of infection and malignancies
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?
LIALDA; multimatrix mesalamine
What do systemic corticosteroids inhibit?
All parts of immune system:
cytokines
prostaglandins
leukotrienes
histamine
recruitment factors
adhesion
What molecular feature of glucocorticoids make them bind with higher affinity to the glucocorticoid receptor
Additional double bond in the A ring
What is the active moiety of the prodrugs azathioprine and mercaptopurine?
6-thioguanine nucleotides
What are the mechanisms of thiopurines?
Inhibition of DNA synthesis
Suppression of T cell dependent immune response
Inhibition of de novo purine nucleotide biosynthesis
What toxicities are seen with 6-thioguanine nucleotides?
severely suppress bone marrow
How does long term, low dose methotrexate treat IBD?
leads to accumulation of adenosine, a lymphotoxic immunosuppressive and anti-inflammatory autocoid; impairs neutrophil chemotaxis
What is the MOA of Cyclosporine?
binds cyclophilin and inhibits calcineurin; inhibits gene transcription of IL-2, IL-3, IFN and other factors produced by T cells
What is the main surfactant used for cyclosporine oral formulations?
Polyoxyl 40 hydrogenated castor oil NF (CREMOPHOR)
What is a concern with polyoxyethylated castor oil
can cause allergic reactions
What is the MOA of Tacrolimus?
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
