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GI Week 2 > Lecture 16: IBD pathophysiology and pharmacology > Flashcards

Lecture 16: IBD pathophysiology and pharmacology Flashcards

1
Q

What is the Epidemiology of CD?

A

Even F:M ratio
15-30 and another peak at 50-60
BIMODAL

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2
Q

Epidemiology of UC?

A

Even F:M ratio

Age of onset is similar to CD

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3
Q

What are the three factors that lead to pathophysiology of IBD?

A
  1. genetic predisposition
  2. microbiome
  3. immune system
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4
Q

What is the gene that leads to CD?

A

NOD2
Also CARD15
3 allele variants that lead to higher association

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5
Q

What does NOD2 do?

A

They are in paneth cells
Mutation leads to decrease in defensins
Defective in sensing bacteria, defective autophagy

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6
Q

What cytokines are involved in both CD and UC?

A

IL-23 and IL-12

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7
Q

What genes associated with autophagy lead to CD or UC?

A

Autophagy = CD and NOT UC

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8
Q

How does microbiome lead to IBD?

A

You need to have bacteria in order for IBD to occur, so it seems that bacteria definitely play a role

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9
Q

What methods can disturb balance of gut bacteria and immune system?

A
  1. pathogenic bacteria
  2. abnormal microbial composition
  3. defective host containment of commensal bacteria
  4. defective host immunoregulation (Treg is activated inappropriately)
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10
Q

What are 4 ways that immune system can be compromised in IBD?

A
  1. defect in innate community
  2. decrease in barrier function
  3. over activation of adaptive immunity
  4. leukocyte trafficking
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11
Q

What can TH17 (treg) is activated by?

A

IL-6, TGF-B, IL-21, 23

Produce cytokines that lead to inflammation and fibroblasts

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12
Q

What environmental factors lead to IBD?

A

Stress
Smoking
Dietary factors

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13
Q

What is the pathology and clinical presentation of CD?

A

Affect any level of GI tract
Focal, chronic inflammation
Most common in terminal ileum
Crypt inflammation with ABSCESS formation
Non-caseating granulomas!!
Grossly, it has skip lesions and cobblestoning
Cobblestoning = coalescence of ulceration with deep, serpiginous ulceration and heaped edematous mucosa adjacent
Crohn’s can have FISTULAS so transmural presentations

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14
Q

What are the penetrating and fibrotic complicatons of CD?

A 
Stricturing from fibrosis
Chronic inflammation = attempt to heal driven by TGF-Beta
Subsequent type 3 deposition
Resultant fibrosis
Stricture formation
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15
Q

What are the pathologic features of UC?

A 
Confined to mucosa
Hyperemia, edema and granular appearance
Starts in rectum and goes proximal
No skip lesions
Crypt abscesses and cryptitis
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16
Q

What is the clinical presentation of IBD?

A
  1. abdominal pain
  2. RLQ tenderness
  3. diarrhea
  4. hematochezia (blood from below)
  5. fever, night sweights
  6. weight loss, malabsorption (in CD)
  7. anemia
  8. elevated WBC
  9. hypoalbuminemia
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17
Q

What are extraintestinal manifestations of IBD?

A

Systemic inflammation that can affect other parts of body

  1. Joints (arthralgia)
  2. Bones (osteopenia)
  3. Dermatologic disorders (erythema nodosum)
  4. Opthalmologic complications (conjunctivitis)
  5. hepatobiliary (gall stones)
  6. Renal (nephrolithiasis, stones, due to fat malabsorption)
  7. HemeOnC, colorectal cancer
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18
Q

What is nephrolithiasis?

A

Calculi in kidney

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19
Q

What is calculi?

A

(a stone)

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20
Q

What is primary sclerosing cholangitis?

A

PSC results in chronic inflammation of intra/extrahepatic ducts of biliary tree
Beading irregularity and structuring of bile ducts
Confers high risk of colorectal cancer (CRC) and cholangiocarcinoma

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21
Q

What is MRCP?

A

Magnetic resonance cholangiopancreatography

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22
Q

Is smoking protective in UC?

A

Yes, but it worsens Crohn’s

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23
Q

What are goals of therapy for IBD?

A
  1. improvement of quality of life
  2. induction of remission
  3. avoidance of surgery
    NO CURE for Crohn’s
    Cure for UC = colectomy
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24
Q

What are indications for more aggressive therapy?

A
  1. tobacco use
  2. perianal or penetrating disease
  3. anemia
25
Q

What is the treatment for mild IBD?

A

Short course glucocorticoids used for induction of remission
5-aminosalicylates (5-ASAs) for UC
Budesonide for CD
Topical steroid for distal disease

26
Q

What is the treatment for mild UC?

A 
5 aminosalicylates (5-ASAs)
immunosuppresant
27
Q

What is the treatment for mild CD?

A

Budesonide

A short course glucocorticoid

28
Q

What is the treatment for moderate to severe IBD?

A

Immunosuppression to promote healing

  1. Immunomodulates like
    i. Thiopurine antimetabolites (Aziathioprine)
    ii. Methotrexate
  2. Anti-TNF agents = Biologics
  3. Anti-alpha4 inhibitors
29
Q

What are the key characteristics of aminosalicylates?

A

5-ASA moiety was therapeutic
If you have the whole thing, you have really bad side effects like agranulocytosis
Preparations of MESALAMINE have been developed to target bowel

30
Q

What is mesalamine?

A

A type of aminosalicylates

31
Q

What is the MoA of aminosalicylate/mesalamine?

A 
Inhibition of T cell proliferation
Inhibition of antigen presentation
Decreased TNF production
Inhibition of adhesion
Used for UC
32
Q

What are the side effects for Aminosalicylates?

A

Paradoxical diarrhea

Interstitial nephritis

33
Q

What are the two main classes of glucocorticoids?

A
  1. Budesonide
  2. systemic corticosteroids like prednisone
    Used more for CD
34
Q

What is the MoA of glucocorticoids?

A
  1. inhibition of pro-inflammatory cytokines, adhesion molecules, leukotrienese
  2. inhibition of proteases such as elastase
  3. regulation of NF-kbeta in the nuclear
  4. decreased phagocytosis for neutrophils
  5. apoptosis of lymphocytes
35
Q

What is the drawback for glucocorticoids?

A

They are not useful for MAINTENANCE of remission

Used instead to induce remission NOT to maintain it

36
Q

What are the side effects of glucocorticoids

A
  1. Neuropsychiatric

2. Cushingoid response

37
Q

What are the key characteristics of Budesonide?

A
  1. Novel steroid compound available in ileal release
  2. high degree of first pass metabolism in the liver
  3. Budesonide has been demonstrated to INDUCE remission in CD
    Standard therapy for mild CD
38
Q

What are the steroid-sparing agents?

A
  1. Immunomodulators
  2. Anti-TNFs
  3. Anti-alpha4 antibodies
39
Q

What are the two types of immune modulaters?

A
  1. Thiopurines

2. Methotrexaate

40
Q

What are the two types of thiopurines?

A
  1. Azithioprine

2. 6MP

41
Q

What is MoA of Azathioprine and 6MP?

A

Act to INHIBIT DNA synthesis
AZA is converted to 6MP
6MP can then enter 3 pathways, one of hwhich converts it to 6-TIMP which inhibits DNA synthesis through apoptosis and inhibition of purine synthesis

42
Q

What is contraindicated in the use of thiopurinols for moderate/severe IBD?

A

The presence of LOW TPMT activity
Some individuals possess a mutation with low TPMT activity
TPMT is an enzyme that converts 6-MP and 6-TIMP to shit that is hepatotoxic and inhibits purine synthesis
Low activity = bone marrow suppression and leukopenia

43
Q

What is TPMT?

A

Thiopurine Methyltransferase

44
Q

What are thiopurines used for?

A

Induction AND maintenance of remission of CD

Couple of months for effect

45
Q

What are adverse effects of thiopurines?

A
  1. leukopenia, marrow suppression
  2. pancreatitis
  3. drug induced hepatitis
  4. infection (but lower risk than steroids)
  5. 3-5x increase risk of NHLymphoma
46
Q

What is the MoA of methotrexate?

A

Folate antagonist
Inhibits multiple interleukins
Anti-inflmmatory properties
Effective for induction and maintenance of CD

47
Q

What are the adverse effects of methotrexate?

A
  1. Nausea
  2. cirrhosis (lung issues)
  3. Teratogenic (induces abnormal prenatal development)
  4. pneumonitis
48
Q

What is the characteristic of cyclosproin A?

A

Used for UC but discontinued for side effects

49
Q

What are the types of anti-TNF therapies?

A
  1. Infliximab (IV)
  2. Adalimumab (subcutaneous)
  3. Certolizumab pegol
50
Q

What is MoA of anti-TNF therapy?

A

Bind both soluble and cell-bound TNFalpha
Direct inhibition of TNF alpha
Induction of apoptosis of T cells and lymphocytes in lamina propria
Complement mediated apoptosis
Alters cytokine secretion in serum and lamina propria
Decrases IL, 1, 6, 18 and IFN gamma

51
Q

What are infliximab, adalimumab and certolizumab used for?

52
Q

What are infliximab and adalimumab used for?

53
Q

What are the side effects of Anti-TNF therapy?

A
  1. transfusion reactions
  2. delayed hypersensitivity reactions
  3. drug induced lupus
  4. infection
  5. screened for Tb, hep b before initiating anti-TNF
  6. Hepatospelnic T cell lymphoma
54
Q

What is the MoA of Anti-alpha4 Integrin inhibitors?

A

Directed against leukocyte adhesion molecules

55
Q

What is an example of anti-alpha4 integrin inhibitor?

A

Natalizumab

56
Q

What are the side effects of anti-alpha4 inhibitors?

A

PML (progressive multifocal leukoencephalopathy) if you have JC virus
Requires screening of JC virus

57
Q

What are antibiotics used for in IBD?

A

Used for penetrating complications for IBD

58
Q

What drug increases risk of PML?

A

Natalizumab (anti-alpha4 inhibitor)

GI Week 2 (15 decks)

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