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LCRS Pharmacology and Therapeutics > Inflammatory bowel disease > Flashcards

Inflammatory bowel disease Flashcards

1
Q

What are the two major forms of IBD?

A 
Ulcerative colitis (UC)
Crohn's disease (CD)
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2
Q

In what percentage of patients is the distinction between UC and CD incomplete?

A

10%

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3
Q

How many people in the UK currently have IBD?

A

300,000

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4
Q

Why is CD more extensively studied?

A

It is more serious and difficult to treat

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5
Q

What are the risk factors for IBD?

A

Genetic predispositions

Environmental factors which could include smoking and diet/obesity (it’s a disease of affluence)

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6
Q

What is obesity a risk factor for?

A

CD but not UC

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7
Q

What is the simple point of the disease’s pathogenesis?

A

Defective interaction between mucosal immune system and gut flora

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8
Q

Explain the basic development of IBD?

A

Complex interplay between host and microbes
Disrupted innate immunity
Uncontrolled inflammation
Physical damage to epithelium and leakiness of tight junctions

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9
Q

What mediates UC?

A

TH2

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10
Q

What is UC dependent on?

A

Cytokines such as IL-5 and IL-13

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11
Q

What does UC tend to affect?

A

Just mucosa and submucosa

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12
Q

Where does UC always start?

A

It always starts in the rectum and spreads proximally- it’s always continuous

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13
Q

How can you cure UC in worst case scenario?

A

Surgery- remove affected piece of bowel and it doesn’t reoccur

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14
Q

What is CD mediated by?

A

TH1

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15
Q

What is the main cytokine in CD?

A

TNF-alpha

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16
Q

What is the effect of CD being TH1 mediated?

A

It causes a more severe inflammatory response

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17
Q

What does CD affect?

A

It can penetrate all the way through the gut and can affect any point of GI tract from mouth to anus

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18
Q

What is the main problem with CD?

A

It causes patchy inflammation which means you can’t remove affected area as easily as UC

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19
Q

What happens if you cut out affected area in CD?

A

It is likely to reoccur

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20
Q

What are you more likely to develop in CD than UC?

A

Abscesses, fissures and fistulae

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21
Q

What is chrohn’s physically characterised by in terms of appearance?

A

Cobblestone appearance

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22
Q

What is a fistula?

A

Abnormal or surgically made passage between a hollow tubular organ and body surface or between two hollow or tubular organs

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23
Q

What are the clinical features of IBD?

A 
Diarrhoea, blood, mucus
Weight loss
Skin rash
Right iliac fossa mass/pain
Primary sclerosing cholangitis
Aphthous ulcers
Anaemia, uveitis, fevers, sweats and jaundice
Abdominal pain
Arthritis arthralgia
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24
Q

What does someone need if they have very bloody diarrhoea?

A

Fluid/electrolyte replacement
Blood transfusion/oral iron
Nutritional support

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25
Q

How is IBD treated?

A

Symptomatically:
Glucocorticoids e.g. prednisolone
Aminosalicylates e.g. mesalazine
Immunosuppressives e.g. azathioprine

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26
Q

What potentially curative therapies are there?

A

Manipulation of gut microbiome
Biological therapies:
Anti-TNF alpha e.g. infliximab
Anti alpha-4-integrin e.g. natalizumab

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27
Q

How effective are aminosalicylates in UC and CD?

A

In UC:
First line inducing and maintaining remission
Good evidence base
Crohn’s disease:
Unsure effectiveness in active disease
May help maintain surgically induced remission
Less clear cut than utility in UC

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28
Q

What is mesalazine?

A

5-aminosalicylic acid (5-ASA)

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29
Q

What is olsalazine?

A

Slightly more complex molecules- consists of 2 linked 5-ASA molecules (no benefit compared to mesalazine)
Anti-inflammatory

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30
Q

What is the mechanism of anti-inflammatory action?

A 
Inhibition of:
-IL-1
-TNF-alpha
-Platelet activating factor (PAF)
Decreased antibody secretion
Non-specific cytokine inhibition
Reduced cell migration (macrophages)
Localised inhibition of immune responses
31
Q

What is anti-inflammatory action more effective in?

A

UC than CD which is weird as it seems to be targeting Th1 and UC is mainly governed by Th2 system

32
Q

What is the pharmacokinetics of 5-ASA derivatives? (mesalazine and olsalazine)

A

Mesalazine doesn’t need to be metabolised so is absorbed in small bowel and colon
Olsalazine is more complex and needs to be activated by colonic flora so is only absorbed in colon

33
Q

What is better between topical 5-ASA and topical steroids at inducing remission in UC?

A

Topical-5-ASA

Combined with steroids is even better

34
Q

Why is the use of glucocorticoids for UC in decline?

A

It has been shown that aminosalicylates are better than glucocorticoids ar doing the job

35
Q

How can glucocorticoids be used?

A

Topically (enema) or IV if severe

36
Q

What are the drugs of choice for inducing remission in Crohn’s?

A

Glucocorticoids but you’re likely to get side effects if they’re used to maintain remission

37
Q

Give some examples of glucocorticoids?

A

Prednisolone, fluticasone and budesonide

38
Q

What are glucocorticoids?

A

Powerful anti-inflammatory and immunosuppressive drugs derived from cortisol that activate intracellular glucocorticoid receptors which then act as positive or negative transcription factors

39
Q

What strategies are there for minimising side effects of glucocorticoids?

A

Topical administration- fluid or foam enemas
Low dose in combination with another drug
Oral or topically administered drug with high hepatic first pass metabolism e.g. budesonide- so relatively little active glucocorticoid escapes into systemic circulation

40
Q

How does budesonide compare to standard glucocorticoids?

A

Budesonide has fewer side effects but standard oral glucocorticoids are better at inducing remission in active Crohn’s disease and budesonide is a little better than placebo at preventing CD relapse

41
Q

How effective have immunosuppressive agents been at inducing remission in UC and CD?

A

A number of drugs have been tried but have not been successful

42
Q

Which immunosuppressive drugs have been tried ad how effective have they been?

A

Azathioprine has shown significant degree of success in UC and CD
Methotrexate has demonstrable efficacy in some IBD patients
Cyclosporin is useful only in severe UC

43
Q

What is azathioprine mainly used for?

A

Maintain remission in CD

44
Q

What is the onset of azathioprine like?

A

Slow- 3-4 months of treat required before clinical benefits seen which can be problematic as patients may relapse between starting treatment and seeing benefits

45
Q

How is azathioprine activated?

A

It is a pro-drug that is activated in vivo by gut flora to 6-mercaptopurine

46
Q

What is 6-mercaptopurine?

A

Purine antagonist so it interferes with DNA synthesis and cell remplication

47
Q

What does 6-mercaptopurine impair and enhance?

A 
It impairs:
Cell and antibody mediated immune responses
Lymphocyte proliferation
Mononuclear cell infiltration
Synthesis of antibodies
It enhances:
T cell apoptosis
48
Q

What percentage of patients on azathioprine have to stop treatment because of side effects?

A

10%

49
Q

What unwanted effects is azathioprine associated with?

A

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

50
Q

How many routes of metabolism are there for azathioprine?

A

3

51
Q

Why don’t you want too much use of the metabolism of azathioprine pathway that involves HRPT?

A

It produces active metabolites that are beneficial but cause myelosuppression

52
Q

Why don’t you want too much use of the metabolism of azathioprine pathway that involves TPMT?

A

It will produce metabolites that aren’t beneficial and hepatotoxic

53
Q

Which pathway is preferred for azathioprine metabolism?

A

Xanthine oxidase- its metabolites are inert so won’t cause any problems

54
Q

What does allopurinol inhibit?

A

Xanthine oxidase

55
Q

What is allopurinol used to treat?

A

Gout

56
Q

What happens if the xanthine oxidase is inhibited?

A

You will shunt azathioprine through other pathways so patients need to be monitored to make sure they aren’t making too many toxic metabolites

57
Q

How effective is azathioprine at maintaining remission in CD?

A

Clear benefit over placebo

58
Q

How effective is methotrexate at maintaining remission in CD?

A

It has a demonstrable effect

59
Q

What does methotrexate do?

A

It is a folate antagonist which reduces the synthesis of thymidine and other purines

60
Q

Why is methotrexate not widely used?

A

There are significant unwanted side effects

61
Q

How effective are nutrition based therapies/probiotics at obtaining and maintaining remission in UC and CD?

A

No evidence for probiotics in CD

Evidence for probiotics in UC

62
Q

What is the rationale for Faecal microbiota replacement therapies (FMT)?

A

There is insufficient evidence for it but rational is gut flora is out of control and there are organisms that you don’t want there causing harm so wipe them out and replace them with good normal microbiota

63
Q

How does antibiotic treatment (rifaximin) have an effect on CD and UC?

A

It induces and sustains remission in moderate CD
It may be beneficial in UC
It interferes with bacterial transcription by binding to RNA polymerase and it reduces the amount of mRNA coding for inflammatory mediators in UC

64
Q

What biological therapies have been approved for use in IBD?

A

Anti-TNF-alpha antibodies:

  • Infliximab (IV)
  • Adalimumab (SC)
65
Q

How effective are anti-TNF alpha antibodies in treating CD?

A

They are used very effectively

66
Q

What percentage of patients will respond within 6 weeks to anti-TNF-alpha antibodies?

A

60% (potentially curative

67
Q

What does refractory disease mean?

A

It describes disease that doesn’t respond to attempted forms of treatment

68
Q

How effective are anti-TNF alpha antibodies in treating UC?

A

Some evidence of effectiveness which is surprising because TNF-alpha is a Th1 cytokine

69
Q

What is the mechanism of action of anti-TNF-alpha antibodies?

A

Anti-TNF alpha reduces activation of TNF-alpha receptors in the gut, TNF-alpha is right at the top of inflammatory cascade so you get general down regulation of other cytokines as well
It also reduces infiltration and activation of leukocytes
Also bind to membrane associated TNF-alpha
Induces cytolysis of cells expressing TNF-alpha
Promotes apoptosis of activated T cells

70
Q

What is the half life of infliximab like?

A

It has a very long half life of 9.5 days which means benefits can last for 30 weeks after a single infusion (most patients relapse after 8-12 weeks so there is a repeat infusion every 8 weeks)

71
Q

What is a big problem with anti-TNF-alpha antibodies?

A

There is emerging evidence showing that upto 50% of responders lose response within 3 years due to production of anti-drug antibodies and increased drug clearance

72
Q

What adverse effects of anti-TNF-alpha antibodies are there and what causes this?

A

All of these are consequences of knocking out the key cytokine in the inflammatory cascade:
4-5x increase in incidence of tuberculosis and other infections
Risk of reactivating dormant TB
Increased risk of septicaemia
Worsening of heart failure
Increased risk of demyelinating disease
Increased risk of malignancy
Immunogenic- azathioprine reduces risk but raises risk of TB/malignancy

73
Q

What was the SONIC study and what did it show?

A

It was a study on infliximab- 500 patients with CD were monitored for 30 weeks- it showed that early use of infliximab in patients with refractory disease is better than last resort. CRP levels and endoscopy might allow identification of patients that are most likely to benefit

LCRS Pharmacology and Therapeutics (33 decks)

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