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Y2 - PHARM > Inflammatory Bowel Disease > Flashcards

Inflammatory Bowel Disease Flashcards

1
Q

What are the two main diseases that come under Inflammatory Bowel Disease?

A
  1. Ulcerative Colitis
  2. Crohn’s Disease
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2
Q

What is the underlying pathogenesis of these diseases based on?

A
  • It boils down to a defective interaction between the mucosal immune system and gut flora
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3
Q

What type of IBD is obesity a risk factor for?

A
  • Crohn’s Disease
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4
Q

Which T cell responses are involved in:

1) Ulcerative Colitis?
2) Crohn’s Disease?

A

1) Ulcerative Colitis - Th2
2) Crohn’s Disease - Th1

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5
Q

What are the main cytokines in:

1) Ulcerative Colitis?
2) Crohn’s Disease?

A

1)

  • Ulcerative Colitis - IL-5, IL-13

2)

  • Crohn’s Disease - TNF-alpha
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6
Q

Which layers of the gut are affected in:

1) Ulcerative Colitis?
2) Crohn’s Disease?

A

1)

  • Ulcerative Colitis - Mucosa + Submucosa

2)

  • Crohn’s Disease - All Layers
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7
Q

Describe which regions of the gut are affected in:

1) Ulcerative Colitis
2) Crohn’s Disease

A

1)

  • Ulcerative Colitis - starts at the rectum and proceeds proximally (continuous inflammation)

2)

  • Crohn’s Disease - can be anywhere on the GI tract (mouth to anus) - patchy inflammation
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8
Q

Are abscesses, fissures and fistulae common in:

1) Ulcerative Colitis?
2) Crohn’s Disease?

A

1)

  • Ulcerative Colitis - No

2)

  • Crohn’s Disease - Yes
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9
Q

Describe the effectiveness of surgery in:

1) Ulcerative Colitis
2) Crohn’s Disease

A

1)

  • Ulcerative Colitis - Curative

2)

  • Crohn’s Disease - Not always curative, even if the affected area is cut out, it often reoccurs
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10
Q

Describe some supportive therapies that are given for IBD

A
  • Nutritional therapy Fluid/electrolytes
  • Potentially even blood transfusions/oral iron
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11
Q

What are the three types of classic symptomatic treatment for IBD?

A
  1. Aminosalicylates
  2. Glucocorticoids
  3. Immunosuppressants e.g. azathioprines
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12
Q

What is the main aminosalicylate drug?

A
  • Mesalazine AKA 5-aminosalicylic acid (5-ASA)
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13
Q

What is a slightly more complex aminosalicylate?

A
  • Olsalazine (this is 2 x 5-ASA)
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14
Q

What type of drug are aminosalicylates?

A
  • Anti-inflammatory
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15
Q

Describe the mechanism of anti-inflammatory action of aminosalicylates

A
  • They inhibit IL-1, TNF-alpha and PAF secreted by dendritic cells
  • Decrease antibody secretion
  • Reduced cell migration (macrophages)
  • Localised inhibition of immune responses
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16
Q

Describe the activation of 2 types of aminosalicylates and thus the sites where they are active

A
  • Mesalazine does not have to be activated any further - all over GI
  • Olsalazine must be activated by colonic flora - only in colon
17
Q

Describe the effectiveness of aminosalicylates in Ulcerative Colitis and Crohn’s Disease

A
  • They are effective at inducing and maintaining remission in UC
  • They are better than steroids at inducing remission in UC
  • They are less effective in CD
18
Q

Describe the use of glucocorticoids in IBD

A
  • Use of glucocorticoids in UC is in decline because aminosalicylates are better
  • Glucocorticoids are still the drug of choice for inducing remission in CD
  • However, side effects are likely if they are used to maintain remission
19
Q

Describe some strategies for minimising the side effects of glucocorticoids

A
  • Topical administration (e.g. enemas and suppositories)
  • Low dose
  • Use oral or topically administered glucocorticoid with a high first pass metabolism
20
Q

What is an example of a glucocorticoid that has relatively few side effects?

A
  • Budesonide
21
Q

Describe the effectiveness of budesonide compared to other glucocorticoids

A
  • Budesonide has fewer side effects than other glucocorticoids but it is less effective at inducing remission in CD
22
Q

State three immunosuppressive agents that could be used in IBD

A
  1. Azathioprine
  2. Methotrexate
  3. Cyclosporin – only useful in severe UC
23
Q

Describe the onset of action of azathioprine

A
  • Slow onset – can take 3-4 months
24
Q

Describe the activation of azathioprine

A

Azathioprine needs to be metabolised by gut flora to 6-mercaptopurine

25
Q

Describe the mechanism of action of azathioprine

A
  • Azathioprine is converted into 6-mercaptopurine
  • 6-mercaptopurine is a purine antagonist. It interferes with DNA synthesis and cell replication. It impairs:
  • Cell- and antibody-mediated immune responses
  • Lymphocyte proliferation
  • Mononuclear cell infiltration
  • Synthesis of antibodies - it enhances T-cell apoptosis
  • 6-mercaptopurine is also converted into 6-MeMPN which inhibits de novo purine synthesis
  • 6-TU which is a ‘fake purine’ which inserts into DNA
26
Q

What are the unwanted effects of azathioprine?

A
  • Pancreatitis
  • Bone marrow suppression
  • Hepatotoxicity
  • Increased risk (4 fold) of lymphoma and skin cancer
27
Q

Describe the metabolism of azathioprine

A

There are three routes of metabolism of azathioprine:

  • Route resulting in the production of beneficial active metabolites that also cause myelosuppression (HPRT pathway produces 6-TIMP –> 6-TGN or 6-MePN)
  • Route resulting in hepatotoxic metabolites with no beneficial effect (TPMT produces 6-MeMP)
  • Xanthine Oxidase Pathway– produces inert metabolites (6-TU). Xanthine oxidase is, fortunately, the main route of azathioprine metabolism
28
Q

In what clinical situation could there be a problem with azathioprine metabolism?

A
  • If the patient is taking allopurinol
  • Allopurinol is used to treat gout and is a xanthine oxidase inhibitor
  • This will result in the azathioprine being shunted down the hepatotoxic and myelosuppressive routes of metabolism, rather than forming the inactive metabolite 6-TU
29
Q

What is the mechanism of action of Methotrexate?

A
  • Folate antagonist
  • It reduces the production of thymidine and other purines
  • NOTE: not widely used because of significant side effects
30
Q

What are the three microbiome manipulation therapies for IBD?

A
  1. Nutrition based therapies – probiotics could be useful in UC
  2. Faecal Microbiota Replacement Therapy (FMT) – could be useful in UC
  3. Antibiotics (Rifaximin) - interferes with bacterial transcription by binding to RNA polymerase. Induces and sustains remission in moderate CD, potentially beneficial in UC
31
Q

Give 2 examples of anti-TNF-alpha antibodies

A
  1. Infliximab (IV)
  2. Adalimumab (SC)
32
Q

Describe the mechanism of action of anti-TNF-alpha antibodies

A
  • Knocking out TNF-alpha leads to general downregulation of other inflammatory cytokines
  • Reduced infiltration and activation of leukocytes
  • Induced cytolysis of cells expressing TNF-alpha
  • Promotes apoptosis of activated T-cells
33
Q

What is a problem with anti-TNA-alpha therapy that may require changes in the treatment guidelines?

A
  • Production of anti-drug antibodies
  • Increased drug clearance
34
Q

What are the adverse effects of anti-TNA-alpha therapy?

A
  • Increased risk of tuberculosis
  • Risk of reactivating dormant TB
  • Increased risk of septicaemia
  • Worsening heart failure
  • Increased risk of demyelinating disease
  • Increased risk of malignancy
  • Can be immunogenic
35
Q

What were the key findings from the SONIC trial?

A
  • Early use of infliximab is better than last resort use in patients with refractory disease
  • CRP levels and endoscopy may allow identification of patients that aremost likely to benefit
  • There is a greater risk of infection and lymphoma

Y2 - PHARM (27 decks)

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