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Pharmacology Year 2 > Inflammatory Bowel Disease > Flashcards

Inflammatory Bowel Disease Flashcards

1
Q

What are the Two Major Forms of Inflammatory Bowel Disease?

A

Ulcerative Colitis
Crohn’s Disease

Note that the distinction is incomplete in ~10% patients (Indeterminate Colitis)

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2
Q

How many gene loci have been identified that are associated with IBD (i.e. genetic predisposition)?
What type of people are most susceptible?

State some important environmental risk factors?

A

201 loci identified

People of White European origin most susceptible

Diet (obesity esp. for Crohn’s), smoking, medication etc.

The combination of genetic and environmental factors => altered gut microbiota

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3
Q

What is the underlying pathogenesis of these diseases based on?

A

Defective interaction between mucosal immune system and gut flora - infection

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4
Q

Which T cell responses are involved in:
Crohn’s Disease
Ulcerative Colitis

A

Crohn’s Disease = Th1

Ulcerative Colitis = Th2

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5
Q

What are the main cytokines in:
Crohn’s Disease
Ulcerative Colitis

A

Crohn’s Disease = TNF-alpha

Ulcerative Colitis = IL-5, IL-13

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6
Q

Which layers of the gut are affected in:
Crohn’s Disease
Ulcerative Colitis

A

Crohn’s Disease = All Layers

Ulcerative Colitis = Mucosa + Submucosa

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7
Q

Describe which regions of the gut are affected in:
Crohn’s Disease
Ulcerative Colitis

Also describe the inflammation in each.

A

Crohn’s Disease:
Can be anywhere on the GI tract (mouth to anus)
Patchy inflammation

Ulcerative Colitis:
Starts at the rectum and spreads proximally
Continuous inflammation

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8
Q

Are abscesses, fissures and fistulae common in:
Crohn’s Disease
Ulcerative Colitis

A

Crohn’s Disease
Yes
Ulcerative Colitis
No

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9
Q

Describe the effectiveness of surgery in:
Crohn’s Disease
Ulcerative Colitis

A

Crohn’s Disease:
Not always curative
Ulcerative Colitis:
Curative

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10
Q

List the clinical features of IBD (systemic as well as local)

A 
Abdominal pain and cramping
Diarrhoea, bloody faeces
Mouth ulcers 
Anaemia
Fever
Arthritic pain 
Skin rashes 
Uveitis
Weight loss
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11
Q

Describe some supportive therapies that are given for IBD

A

Nutritional therapy
Fluid/electrolytes
Blood transfusions/oral iron

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12
Q

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

A

Aminosalicylates
Glucocorticoids
Immunosuppressants

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13
Q

What is the main aminosalicylate drug?

A

Mesalazine or 5-aminosalicylic acid (5-ASA)

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14
Q

What is a slightly more complex aminosalicylate?

A

Olsalazine (2 linked 5-ASA molecules)

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15
Q

What type of drug are aminosalicylates?

A

Anti-inflammatory

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16
Q

Describe the mechanism of anti-inflammatory action of aminosalicylates.

A

They inhibit IL-1, TNF-alpha and PAF (inhibit transcription)
=> Decrease antibody secretion
=> Reduced cell migration (macrophages)
=> Localised inhibition of immune responses

17
Q

Describe the activation and site of absorption of the two aminosalicylate drugs.

A

Mesalazine does not have to be activated any further; absorbed in small bowel and colon.
Olsalazine must be activated by colonic flora; absorbed in the colon.

18
Q

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

A

Aminosalicylates and UC:

  • Effective at induction and maintenance of remission
  • Rectal delivery better for localised disease

Aminosalicylates and CD:
- Ineffective in inducing remission of CD

19
Q

Give examples of glucocorticoid drugs used to treat IBS.

What type of drug are they?

A

Examples: Prednisolone, Fluticasone, budesonide

Powerful anti-inflammatory and immunosuppressive drug

20
Q

What is an example of a glucocorticoid that has relatively few side effects, and why is this so?
Describe the effectiveness of budesonide compared to other glucocorticoids.

A

Budesonide

Because it is metabolised and inactivated locally

less effective at inducing remission in CD

21
Q

How could you minimise the side effects of glucocorticoids?

A

Use oral or topically administered glucocorticoid with a high first pass metabolism

22
Q

Describe the use of glucocorticoids in IBD (CD and UC)

A

Ulcerative colitis:
- Strong evidence that aminosalicylates superior

Crohn’s Disease:
- GCs are the drugs of choice for inducing remission

23
Q

State three immunosuppressive agents that could be used in IBD.

A

Azathioprine
Methotrexate
Cyclosporin – only useful in severe UC

24
Q

Describe the onset of action of azathioprine.

A

Slow onset – can take 3-4 months

25
Q

Describe the metabolism/activation of azathioprine.

A

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

26
Q

Describe the mechanism of action of azathioprine - type of drug, does what, impairs what, enhances what?

A 
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
27
Q

What are the unwanted effects of azathioprine?

A
  • Nearly 10% of patients stop treatment because of the side effects
  • Pancreatitis
  • Bone marrow suppression
  • Hepatotoxicity
  • Increased risk of lymphoma and skin cancer
28
Q

What are Azathioprine or other immunosuppressants recommended/ not recommended for?

A

Not recommended for active disease

Recommended for maintaining remission

29
Q

Describe the metabolism of azathioprine.

A

There are three routes of metabolism of azathioprine

  • Route resulting in the production of beneficial active metabolites but also cause myelosuppression (HPRT pathway produces 6-TIMP => 6-TGN)
  • Route resulting in hepatotoxic metabolites with no beneficial effect (TPMT produces 6-MMP)
  • Xanthine Oxidase Pathway– produces inert metabolites (6-TU); main route
30
Q

What are the three potential mechanisms of manipulating the gut microbiome as a potentially curative therapy of IBD?

A

Nutrition based therapies (exclusive enteral nutrition) – probiotics could be useful in UC
Faecal Microbiota Replacement Therapy (FMT) – could be useful in UC

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-𝛼 antibodies (biologic curative therapies)
Include each ROA

A

Infliximab (IV)

Adalimumab (SC)

32
Q

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

A

Anti-TNFa reduces activation of TNFa receptors in the gut
=> Reduces downstream inflammatory events
=> Binds to membrane associated TNFa
=> Induces cytolysis of cells expressing TNFa
=> Promotes apoptosis of activated T cells

33
Q

Describe the pharmacokinetics of infliximab

A

Given intravenously
Long half-life – 9.5 days
Most patients relapse between 8-12 weeks
Repeat infusion given after 8 weeks

34
Q

Describe the effectiveness of anti-TNF- antibodies in Crohn’s Disease.

A
  • Used successfully in the treatment of CD - potentially curative, but many patients relapse
  • Very good for maintaining fistula closure
35
Q

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

A

Evidence showed up to 50% of responders stopped responding after 3 years
This is due to production of anti-drug antibodies and increased drug clearance

36
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
37
Q

Give details on when infliximab should be used and how.

A
  • Early use better than last resort

- Combined infliximab and azathioprine therapy recommended rather than monotherapy

Pharmacology Year 2 (32 decks)

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