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Pharmacology And Therapeutics > Inflammatory Bowel Disease > Flashcards

Inflammatory Bowel Disease Flashcards

1
Q

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

A

Ulcerative Colitis

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 immunesystem 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:

a. Ulcerative Colitis
b. Crohn’s Disease

A

a. Ulcerative Colitis
Th2 - limited clonal expansion, normal T cell apoptosis
b. Crohn’s Disease
Th1 - florid T cell expansion, defective T cell apoptosis

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5
Q

What are the main cytokines in:

a. Ulcerative Colitis
b. Crohn’s Disease

A 
a. Ulcerative Colitis
IL-5
IL-13
b. Crohn's Disease
TNF-alpha
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6
Q

Which layers of the gut are affected in:

a. Ulcerative Colitis
b. Crohn’s Disease

A

a. Ulcerative Colitis
Mucosa + Submucosa
b. Crohn’s Disease
All Layers

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7
Q

Describe which regions of the gut are affected in:

a. Ulcerative Colitis
b. Crohn’s Disease

A

a. Ulcerative Colitis
Starts at the rectum and proceeds proximally (continuous inflammation)
b. 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:

a. Ulcerative Colitis
b. Crohn’s Disease

A

a. Ulcerative Colitis
No
b. Crohn’s Disease
Yes

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9
Q

Describe the effectiveness of surgery in:

a. Ulcerative
b. Crohn’s Disease

A

a. Ulcerative Colitis
Curative
b. 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

Aminosalicylates
Glucocorticoids
Immunosuppressants

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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 
Modulates transcription and downregulates the production of pro-inflammatory cytokines and prostaglandins
They inhibit IL-1, TNF-alpha and PAF  
Decrease antibody secretion  
Reduced cell migration (macrophages) 
Localised inhibition of immune responses
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16
Q

Describe the activation of aminosalicylates.

A

Mesalazine does not have to be activated any further

Olsalazine must be activated by colonic flora

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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
Ineffective in inducing remission of CD.
A very modest amount of evidence for effectiveness in maintenance, and other therapies are preferable in CD

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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. Budesonide preferred if mild.
However, avoid as maintenance therapy due to side effects.

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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 - NOT ABSORBED and tends to stay in the gut

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

Azathioprine
Methotrexate
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

6-mercaptopurine is a purine antagonist
It interfered 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

26
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 (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)
 Route resulting in hepatotoxic metabolites with no beneficial effect (TPMT produces 6-MMP)
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

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 potential mechanisms of manipulating the gutmicrobiome?

A

1 . Exclusive enteral nutrition (EEN)

  • Liquid diet
  • Allows “resting” of the mucosa and recovery of the gut flora
  • Unpalatable and hard to maintain
  • Only recommended for induction of remission if patient cannot take steroids

2 . Nutrition based therapies – probiotics could be useful in UC - Different organisms have different effects so difficult to generalise

  • No evidence for probiotics in CD.
  • Weak evidence for maintenance of remission in UC
  1. Faecal Microbiota Replacement Therapy (FMT) – could be useful in UC
    - 2 of 3 RCTs showed benefit in UC
    - Unclear if changed microbiome is cause or effect
  2. Antibiotics – Rifaximin
     o Interferes with bacterial transcription by binding to RNA polymerase – reduces mRNA coding by inflammatory mediators.
     Induces and sustains remission in moderate CD
     Potentially beneficial in UC
31
Q

Give 2 examples of anti-TNF-alpha (anti-tumour necrosis factor alpha) antibodies.

A

Infliximab (IV)

Adalimumab (SC)

32
Q

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

A

60% of patients will respond within 6 weeks are
it is potentially curative but many patients will relapse
Successful in some patients with refractory disease and fistulae
Very good for maintaining fistula closure

33
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

34
Q

Describe the pharmacokinetics of anti-TNF-alpha antibodies.

A

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

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

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

38
Q

What are some of the clinical features of IBD?

A 
Abdominal pain and cramping
Diarrhoea , bloody faces, 
Mouth ulcers
Anaemia
Fever
Arthritic pain
39
Q

Where is

a) mesalazine
b) olsalazine

Metabolised and absorbed?

A

-

40
Q

Name some examples of glucocorticoids

A

Prednisolone, Fluticasone, budesonide

41
Q

What kind of drugs are glucocorticoids?

A

Powerful anti-inflammatory and immunosuppressive drugs

42
Q

What are glucocorticoids derived from?

A

Hormone cortisol

43
Q

How does glucocorticoids work?

A

Activate intracellular Glucocorticoid Receptors which can then act as positive or negative transcription factors

44
Q

Describe the use of azathioprine in IBD.

A

Not recommended for active CD.
Azathioprine or other immunosuppressants recommended for maintaining remissionIn CD
Glucocorticoid-sparing
•Slow onset – 3 to 4 months treatment for clinical benefit
•If ineffective move to biological therapies

45
Q

What are some strategies for targeted drug delivery?

A

pH dependent polymer coating system
Pressure/osmotic controlled coating system
Time dependent polymer coating system
Prodrug based conjugates
Complex polymers that combine time and pH

Pharmacology And Therapeutics (9 decks)

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