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YEAR 2 PHARM WITH ADDITIONS > 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. Begins as infection. Defective interaction results in physical damage and chronic inflammation

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3
Q

What type of IBD is obesity a risk factor for, and seems to have a genetic component? what other risk factors are there?

A

Crohn’s Disease (201 loci identified)

- smoking, diet, microbiome

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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
b. Crohn’s Disease
Th1

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5
Q

What are the main cytokines, expansion and apoptsis in:

a. Ulcerative Colitis
b. Crohn’s Disease

A

a. Ulcerative Colitis
IL-5
IL-13
Limited conal expansion and normal T cell apoptosis
b. Crohn’s Disease
TNF-alpha (IL-17,23)
Florid T cell expansion and defective t cell apoptosis

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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 (mesalazinem olsalazine)
Glucocorticoids (prednisolone)
Immunosuppressants (Azathioprine)

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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.??? query card???

A

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, first line Tx
They are better than topic steroids at inducing remission in UC
- combining oral and topical 5-ASA is better than oral alone
They are less effective in CD

18
Q

Describe glucocorticoids, and their use in IBD.

A
  • Glucocorticoids (prednisolone, fludrocortisole, budesonide) are derived from hormone cortisol (therefore have multiple side effects if given systemically)
  • they are powerful antinflam and immunosuppressive drugs.
  • Act by activating intracellular glucocorticoid receptors which can then act as positive or negative TFs
  • they can inhibit the production of IL-1 and TNF-a by dendritic cells, dendritic cells are thought to play a big part in IBD

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 is used if disease is mild as has fewer sidde effects as extensive hepatic first pass metabolism therefore little gets into systemic circulation)
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. fluid, foam enemas and suppositories, fluid, oral preperations) 
Low dose  (combined with other medication eg mesalazine)
Use oral or topically administered glucocorticoid with a high first pass metabolism (eg Budesonide, therefore little escapes into the systemic circulation)
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 than prednisolone

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

  • 6MP can be metabolised into variety of things too, 2 active and 2 inactive forms
  • active forms are 6-MeMPN: inhibits denovo purine synthesis
  • 6-TGN: acts like false purine and gets incorperated into DNA
25
Q

Describe the mechanism of action of azathioprine, and clinical use of Azothioprine

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

Uses:

  • UC: some success but no real reason to use if had success with 5-ASA
  • CD: no benefit in active disease, mainly used to maintain remission. Shown to be glucocorticoid sparing
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 4 routes of metabolism of azathioprine
 Route resulting in the production of beneficial active metabolites that also cause myelosuppression (HGPRT pathway produces 6-TIMP –> 6-TGN ( other path varient produces or 6-MeMPN)
 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

Nutrition based therapies – probiotics could be useful in UC, as useful in 5-ASA as inducing remission, no evidence of impact in CD
Faecal Microbiota Replacement Therapy (FMT) – could be useful in UC, more studies needed

Antibiotics – Rifaximin
 Interferes with bacterial transcription by binding to RNA polymerase
 Induces and sustains remission in moderate CD
 Potentially beneficial in UC
- rifaximin reduces inflammatory mediator mRNA in experiental coloitis

31
Q

Give 2 examples of anti-TNF-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

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 two pathways regulate inflammation and how do they work?

A

NF-KB/MAPK: down regulate pro inflammatory cytokines

COX2: down-regulates prostaglandins

39
Q

what new targets are potentially being investigated?

A 
integrins (needed for cells to migrate)
interleukins (IL12,17,23)
Interleukin receptors
Janus Kinase (JAK) cytoplasmic cell signalling
40
Q

Summary of therapy types in IBD

A

Supportive Treatments/therapies: fluids/electrolytes, nutritional support, blood)
Symptomatic treatments: both for active disease and remission prevention (bulk of IBD tx)
Curative Treatments: surgery, microbiome manipulation, biologic therapies (anti-TNFa: eg infliximab (monoclonal antibody to TNF-a))

41
Q

what pathways is inflammation regulated by?

A

NF-KB/MAPK: down-regulates proinflammatory cytokines: TNF-a, IL-1B, IL-6
COX-2 pathway: down-regulates prostaglandins - PGE2 and PGF2

YEAR 2 PHARM WITH ADDITIONS (33 decks)

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