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Pharmacology > Inflammatory bowel disease > Flashcards

Inflammatory bowel disease Flashcards

1
Q

What are the 2 main forms of inflammatory bowel disease?

A

Ulcerative colitis
Crohn’s disease
Distinction incomplete in around 10% of patients- indeterminate colitis

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2
Q

How many people are affected by inflammatory bowel disease in the UK?

A

300,000

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3
Q

What are the genetic risk factors for inflammatory bowel disease?

A

Genetic predisposition
201 loci identified
People of White European origin are most susceptible
Causes incompletely understood

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4
Q

What are the environmental risk factors for inflammatory bowel disease?

A 
Smoking
Diet
Microbiome
Medication
Sleep 
Stress
Physical activity
Air pollution
UV exposure/ vitamin D
Appendectomy
Heavy metal
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5
Q

What type of disease is IBD and how does it arise?

A

Autoimmune.
Defective interaction between mucosal immune system and gut flora- infection.
10x more gut bacteria than host cells.
Complex interplay between host and microbes.
Disrupted innate immunity and impaired clearance.
Pro-inflammatory compensatory response.
Physical damage and chronic inflammation.

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6
Q

What are the supportive therapies for acutely sick IBD patients?

A

Fluid/electrolyte replacement
Blood transfusion/ oral iron
Nutritional support (malnutrition common)

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7
Q

What are the symptomatic therapies for active IBD?

A

Glucocorticoids, e.g. prednisolone
Aminosalicylates, e.g. mesalazine
Immunosuppressives, e.g. azathioprine

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8
Q

What are the symptomatic therapies for prevention of remission of IBD?

A

Glucocorticoids, e.g. prednisolone
Aminosalicylates, e.g. mesalazine
Immunosuppressives, e.g. azathioprine

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9
Q

What are the potentially curative therapies for IBD?

A

Microbiome manipulation

Biologic therapies

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10
Q

Give 2 examples of aminosalicylates.

A

Mesalazine or 5-aminosalicylic acid (5-ASA)
Olsalazine (2 linked 5-ASA molecules)
Anti-inflammatory.

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11
Q

What are the differences between mesalazine and olsalazine?

A

Olsalazine is metabolised by colonic flora so is only absorbed in the colon, whereas mesalazine can be absorbed in the small intestine and the colon.
Olsalazine is 2 linked 5-ASA molecules, whereas mesalazine is one 5-ASA molecule.

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12
Q

How do aminosalicylates have their anti-inflammatory actions?

A

Down-regulate NF-kappa-B/MAPK pathways to reduce pro-inflammatory cytokines: TNF-alpha, IL-1-beta, IL-6.
Down-regulate COX-2 pathway to reduce prostaglandins: PGE2, PGF2.

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13
Q

What is the utility of aminosalicylates in ulcerative colitis?

A

First line treatment for inducing and maintaining remission.

Good evidence base.

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14
Q

What is the utility of aminosalicylates in Crohn’s disease?

A 
Literature unclear.
Ineffective in inducing remission.
Less clear cut than utility in UC.
Glucocorticoids probably better.
May be effective in a subgroup of patients.
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15
Q

Give 3 examples of glucocorticoids.

A

Prednisolone
Fluticasone
Budesonide

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16
Q

What are glucocorticoids?

A

Powerful anti-inflammatory and immunosuppressive drugs.

Derived from the hormone cortisol.

17
Q

How do glucocorticoids work?

A

Activate intracellular glucocorticoid receptors which can then act as positive or negative transcription factors.

18
Q

What strategies exist for minimising the unwanted effects of glucocorticoids?

A

Administer topically- fluid or foam enemas or suppositories.
Use a low dose in combination with another drug.
Use an oral or topically administered drug with high hepatic first pass metabolism, e.g. budesonide, so little escapes into the systemic circulation.

19
Q

What is the utility of glucocorticoids in ulcerative colitis?

A

Use of glucocorticoids in decline.
Evidence that aminosalicylates superior.
Glucocorticoids best avoided.

20
Q

What is the utility of glucocorticoids in Crohn’s disease?

A

GCs remain drugs of choice for inducing remission.
Budesonide preferred if mild.
Likely to get side effects if used to maintain remission.

21
Q

What is azathioprine?

A

A prodrug activated by gut flora to 6-mercaptopurine.
Give 6-mercaptopurine directly.
Purine antagonist.
Immunosuppressive.

22
Q

How does azathioprine work as an immunosuppressive?

A

Once activated to 6-mercaptopurine, interferes with DNA synthesis and cell replication.
Inhibition of de novo purine synthesis.
Incorporation into DNA.

23
Q

What are the effects of azathioprine on the immune system?

A 
Impairs cell- and antibody-mediated immune responses.
Impairs lymphocyte proliferation.
Impairs mononuclear cell infiltration.
Impairs synthesis of antibodies.
Enhances T cell apoptosis.
24
Q

What is the utility of azathioprine in ulcerative colitis?

A

Some success.

25
Q

What is the utility of azathioprine in Crohn’s disease?

A

No benefit in active disease.
Mainly used to maintain remission.
Recent Cochrane review shows it to be glucocorticoid-sparing.
Slow onset- 3 to 4 months treatment for clinical benefit.

26
Q

What are the unwanted effects of azathioprine?

A

Nearly 10% patients have to stop treatment because of side effects.
Pancreatitis.
Bone marrow suppression.
Hepatotoxicity.
Increased risk (around 4-fold) of lymphoma and skin cancer.

27
Q

What are the 3 types of potentially curative therapies for IBD involving manipulation of the microbiome?

A

Nutrition-based therapies:
-no evidence for probiotics in CD
-some evidence for probiotics for maintenance of remission in UC
Faecal microbiota replacement (FMT) therapies:
-insufficient evidence for FMT
-2 of 3 RCTs showed benefit in UC
-more studies needed
Antibiotic treatment- rifaximin:
-interferes with bacterial transcription by binding to RNA polymerase
-induces and sustains remission in moderate CD
-may be beneficial in UC
-may be microbiome modulator

28
Q

What is the significance of biologic therapies in IBD?

A

Approved for use in IBD.
Anti-TNF-alpha antibodies.
Example: infliximab (i.v.)
Other antibodies effective but some have more side-effects.
New humanised antibodies coming on stream, e.g. entanacept.

29
Q

What is the mechanism of anti-TNF-alpha antibodies in IBD treatment?

A

Anti-TNF-alpha reduces activation of TNF-alpha receptors in the gut.
Reduces downstream inflammatory events.
Also binds to membrane associated TNF-alpha.
Induces cytolysis of cells expressing TNF-alpha.
Promotes apoptosis of activated T cells.

30
Q

Discuss the pharmacokinetics of infliximab (anti-TNF-alpha antibody).

A

Given intravenously.
Very long half-life (9.5 days).
Most patients relapse after 8-12 weeks.
Therefore repeat infusion every 8 weeks.

31
Q

What is the utility and significance of anti-TNF-alpha antibodies in treatment of IBD?

A

Used successfully in CD treatment.
Only 60% patients respond within 6 weeks.
Potentially curative, but many patients relapse.
Successful in some patients with refractory disease and fistulae.
Very good for maintaining fistula closure.

32
Q

What are the problems with anti-TNF-alpha antibodies in treatment of IBD?

A

Emerging evidence that up to 50% responders lose response within 3 years time due to production of anti-drug antibodies and increased drug clearance.
Attempts being made to optimise dosing regimens.

33
Q

What are the adverse effects associated with anti-TNF-alpha antibodies in treatment of IBD?

A

4-5x increase in incidence of tuberculosis
Also risk of reactivating dormant TB
Increased risk of septicaemia
Worsening of heart failure
Increased risk of demyelinating disease
Increased risk of malignancy
Can be immunogenic- azathioprine reduces risk, but raises TB/malignancy risk

34
Q

What are some new targets for treatment of IBD?

A

Integrins (needed for cells to migrate)
Interleukins (IL-12, IL-17, IL-23)
Interleukin receptors
Janus kinase (JAK) cytoplasmic cell signalling

Pharmacology (21 decks)

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