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Module 3: IBD Digavalli Flashcards

Dr, Digavalli EXAMV

1
Q

Affected areas of Inflammatory Bowel Disease (IBD) vs Crohn’s disease

A

IBD: starts in the rectum -> may affect the entire colon continuously

Crohn’s disease: non-continuous, patchy areas, often the ileocecal junction; may affect large or small intestine

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2
Q

Which layers of the tissues are affected?

A

IBD: superficial -> limited to the mucosal layer

Crohn’s: affects multiple layers -> may lead to strictures, perforation, fistula formation

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3
Q

Characteristics of Crohn’s disease

A

-skip lesions or cobblestone patterns
-transmural lesions: affecting multiple layers -> leading to strictures, perforation, fistula

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4
Q

What are diseases that arise as a consequence of IBD?

A

-risk of colorectal cancer (regular colonoscopy recommended)
-Extra GI:
skin
dry eyes
Arthropathy
Arthritis
thromboembolic events
stricture of the bile duct (in Chron’s disease)

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5
Q

Disease progression in IBD

A

-symptoms wax and wane but with gradual damage to the GI with each episode (flares)
-damage: strictures, fistula, abscesses

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6
Q

Possible progression to IBD

A
  1. Genetic predisposition and environmental factors (hygiene, diet, smoking)
  2. disease: infection, drug use (NSAIDs damaging the gut wall or antibiotics killing good bacteria) ->
  3. bacteria crossing the wall and causing an inflammatory reaction -> uncontrolled immune response (interleukin, TNF)
  4. bowel damage, tissue remodelling -> IBD
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7
Q

Mild treatment options

A

-5-amino salicylates (5-ASA; mesalamine)
-topical corticosteroids (proctitis)
-budesonide (ileitis)
-antibiotics

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8
Q

5-amino salicylates (mesalamine)

A

-for mild IBD
-MOA not clear
-works locally in the gut

-Sulfasalazine is broken down to 5-ASA (mesalamine) ->
-5-ASA forms an azo linkage -> 5-ASA derivates which is not very well absorbed (stays in the GI)

-bacteria’s azole reductase breaks up the azole linkage -> RELIEF

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9
Q

What is the supposed MOA of 5-ASA

A

-prostanoid release -> NFκB suppression
-NFκB stimulates cytokine production

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10
Q

Which drug has different formulations to target specific areas of the GI?

A

5-ASA derivates
DDS approaching such as enteric coating (protection against gastric dissolution or early release in the small intestine)

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11
Q

MOA of Glucosteroids

A

-binds glucocorticosteroid receptor -> deactivating transcription factors
-prevents the synthesis of inflammatory proteins
-suppress inflammatory signals (NFκB)

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11
Q

What is the severity of IBD treated with glucocorticoids?

A

Mild, moderate IBD
moderate/severe flares
-after treating flares -> patients switch to other drugs bc of the side effect profile

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12
Q

Side effects of Glucocorticosteroids

A

-susceptibility to infections (due to immune suppression)
-interfere glucose metabolism -> gluconeogenesis from non-carbon source -> increases glucose level
-lipid levels go up (via lipolysis)-> arteriosclerosis
-Cushing syndrome (moon face)

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13
Q

Other side effects of steroids

A

-Hypothalamus -Pituitary gland -Adrenal medulla axis -> constant cortisol release -> HPA insufficiency bc the steroid mimics the cortisol -> the body thinks there is enough cortisol and stops producing cortisol (inhibiting the HPA-axis), may cause depression

-osteoporosis
-glaucoma
-muscle myopathy
-hirsutism
-skin breakage
-gastric ulcer (with NSAIDs)

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14
Q

Glucocorticoids drugs

A

Oral, IV when severe
-Prednisone (prodrug)
-Prednisolone (active part)
-Budesonide (synthetic, less systemic due to high first-pass metabolism)

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15
Q

Why is budesonide often preferred over prednisone(prednisolone?

A

-higher metabolism by 3A4 (avoid grape juice)
-less systemic effects
-the effect on cortisol level is less -> lowering the risk of HPA insufficiency

16
Q

Which drugs are substituted with steroid drugs

A

Purine anti-metabolites (azathioprine and 6-MP)

-also for steroid-resistant/dependent patients
-maintain remission while transitioning from steroids
-take weeks to be efficacious

17
Q

MOA of purine anit-metabolites

A

-interfering with fast-dividing white blood cells
-mimic adenine and guanine

azathioprine (prodrug) ->
6-mercapto purine (prodrug) -> 6-thioguanine (active drug)

18
Q

How does Xanthine oxidase affect Purine anti-metabolites?

A

-Purines are metabolized by Xanthine oxidase in the liver
-XAO processes DNA breakdown products into uric acid -> which deposits in joints causing GOUT

-DDI in gout/hyperuricemia patients taking Allopurinol (purine analog) blocking XAO -> less purine antimetabolite metabolism -> higher concentration and TOXICITY
-> reduce dose by 25%

19
Q

Contraindications of Purine-antimetabolites

A

Pregnancy
since they interfere with DNA synthesis

20
Q

MOA of Methotrexate

A

-Anti-metabolite of folic acid (IBD, cancer,..) - mimics folic acid
-interferes with folic acid metabolism: used to synthesize DNA
-Methotrexate interferes with DNA synthesis by blocking the dihydrofolic acid reductase

(also used in adjunction for biologics -> preventing Antidrug-antibodies (ADA))

21
Q

MOA of Cyclosporine

A

-Inhibits Calcineurin (Ca++/Cam-dependent
phosphatase) involved in immune signaling
-not first line
-used to bridge from steroids

22
Q

Which drugs are used for steroid transitioning?

A

-Purine anti-metabolites: azathioprine and 6-MP)
-Methotrexate
-Cyclosporine (short-time bride to 6-MP)

23
Q

What is the role of TNF, INF and interleukins?

A
  1. dendritic cells -> antigen presentation to CD4 TH cells
  2. IL12/23 for TH differentiation -> Th1 and Th2 are pro-inflammatory (via IFN-gamma and IL- 12/4) and Treg is anti-inflammatory (via TGF-ß and IL-6)
  3. TNF-alpha and IFN-gamma for macrophage activation
  4. integrins for lymphocyte and monocyte migration from the blood
24
Q

What severity of IBD is treated with anti-TNFs?

A

-moderate to severe flares in IBD
-patients resistant to other therapies

-neutralize soluble and tmTNF
-all mAbs are parenterally (IV, SC)

-cleared by proteolysis
-latent infection may activated (TB (give prophylactic INH), fungal infections)

25
Q

What happens to the affected cell when anti-TNF binds to tmTNF?

A

complement fixation and cell lysis

26
Q

What mitigates the efficacy of anti-TNFs over time?

A

Antidrug-antibodies (ADA)
-co-administration with methotrexate may help
-switch to another anti-TNF (mAb)

27
Q

How do anti-integrins work?

A

-integrins are present on lymphocytes
-TNF stimulates selectin synthesis in endothelial cells

-lymphocytes will bind to selectins and stop at the site of infection

-anti-integrins-antibodies block the integrin-selectin interaction -> no homing of lymphocytes

28
Q

Examples of anti-integrins

A

-Natalizumab (Tysabri)
-Vedolizumab

-only used when other anti-TNFs don’t work
-approved for MS and Crohn’s disease (reduces inflammation)

29
Q

Which side effect to look out for in anti-integrins

A

-multifocal leuko-encephalopathy (not common)
(infection of the gray matter in the brain)

-Vedolizumab doesn’t cause it

30
Q

Which drug class does Ustekinumab belong to?

A

anti-IL 12/23 mAb

-IL12/23 for TH differentiation
-2nd line drug for Crohn’s disease (when steroids and anti-TNF failed)
-low risk of latent infection activation

31
Q

What drug class does Tofacitinib (Xelijanz) belong to?

A

Janus Kinase (JAK) inhibitors
-inhibits the JAK/STAT pathway (prevents phosphorylation and translocation of STAT into the nucleus)
-downregulates the production of cytokines
-it is NOT an antibody

-for Ulcerative Colitis

-can activate latent infections

32
Q

Which drugs may activate latent infections?

A

-anti-TNFs (Infliximab, Adalimumab, Certolizumab, Golimumab)
-Tofacitinib (Xelijanz) - JAK/STAT inhibitors

33
Q

Common drugs causing a decrease in microbiome diversity

A

-PPIs
-Metformin
-Antibiotics
-NSAIDs
-Laxative

34
Q

Countering bacterial dysbiosis

A

-Prebiotic: food for probiotics
Asparagus, Banana, garlic, wheat bran

-Probiotics contain “good” gut bacteria:
E. coli, Lactobacilli, Bifidobacteria found in
-> Yogurt, sour cream, probiotic milk, kefir

GI (19 decks)

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