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Year 2 - LCRS - Pharmacology > The Pharmacology of Inflammatory Bowel Disease (10.02.2020) > Flashcards

The Pharmacology of Inflammatory Bowel Disease (10.02.2020) Flashcards

1
Q

What are the 2 main forms of IBD?

A
  • Ulcerative Colitis (UC)
  • Crohn’s Disease (CD)
  • Distinction incomplete in ~10% patients (Indeterminate Colitis)
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2
Q

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

A
  • 300,000 people in the UK
  • affects children, adolescents and adults
  • about double incidence in west compared to Eastern Europe which suggests that there are environmental factors involved.
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3
Q

Genetic risk factors for IBD

A
  • Causes incompletely understood
  • CD more extensively studied than UC
  • Genetic predisposition
    • 201 loci identified
    • People of White European origin most susceptible
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4
Q

Which group of people is most susceptible to Crohn’s disease?

A

People of white European origin

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5
Q

What are the environmental risk factors for IBD?

A

Strong Evidence:

  • smoking
  • medication
  • diet
  • sleep
  • stress
  • physical activity
  • air pollution
  • UV light exposure and vitamin D
  • appendectomy
  • heavy metal
  • microbiome: other RFs might have their effects through the microbiome
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6
Q

Microbiome in IBD

A
  • the microbiome is different in patients with IBD
  • is it a cause or a consequence?
  • do they get IBD because of the microbiome or is the differenent microbiome due to IBD
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7
Q

IBD as an autoimmune disease

A
  • there is defective interaction between the mucosal immune system and the gut flora - infection
  • usually there are 10x more bacteria in our gut than host cells

Progress:

  1. Complex interplay between host and microbes
  2. Disrupted innate immunity and impaired clearance
  3. Pro-inflammatory compensatory responses
  4. Physical damage and chronic inflammation
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8
Q

What is the normal interaction of bacteria in the gut like?

A

There are three main types of bacteria:

  • commensal bacteria
  • anti-inflammatory bacteria
  • pathogens
  • in IBD there is disturbance in their interaction (can have causes like diet and environmental) -> higher proportion of pathogenic bacteria
  • the pathogenic bacteria may enter the lamina propria
  • thinning of the mucous layer?
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9
Q

What layers of the gut wall are affected in CD and UC?

A

CD: all layers

UC: mucosa and submucosa

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10
Q

Which regions of the gut are affected in UC and CD?

A

CD: any part of GI

UC: rectum, spreading proximally

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11
Q

How are the inflamed parts disteibuted in CD and UC?

A

CD: patchy

UC: continous

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12
Q

Surgery in CD and UC

A

CD: usually not curative

UC: curative

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13
Q

Absesses, fissures and fistulas in CD and UC

A

CD: common

UC: not common

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14
Q

Nature of the AI disease in CD and UC?

A

CD: Th1 mediated; florid T-cell expamsion with poor clearance (defective T-cell apoptosis)

UC: Th2 mediated, T-cell expansion does not get that much out of control, normal T-cell apoptosis.

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15
Q

Clinical features of IBD

A
  • Abdominal pain and cramping
  • Diarrhoea, bloody faeces (you might have mucous in stool)
  • Mouth ulcers
  • Anaemia
  • Fever
  • Arthritic pain
  • Skin rashes
  • Uveitis
  • Weight loss

The systemic features you are more likely to get in Crohn’s disease.

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16
Q

What are the main categories of therapies in IBD?

A

a) supportive (fluids, blood, nutritional support)
b) symptomatic in active disease (glucocorticoids, aminosalicylates, immunosuppressives)
c) symptomatic in prevention of remission (glucocorticoids, aminosalicylates, immunosuppressives)
d) potentially curable (microbiome manipulation, biologic therapies)

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17
Q

Supportive therapies in IBD

A
  • for the acutely sick patient
    • Fluid/electrolyte replacement
    • Blood transfusion/ oral iron
    • Nutritional support (malnutrition common)
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18
Q

What is used in classic symptomatic treatment of IBD?

A

Active disease and prevention of relapse

  • Aminosalicylates eg Mesalazine
  • Glucocorticoids eg Prednisolone
  • Immunosuppressives eg Azathioprine
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19
Q

Aminosalicylates

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

5-ASA can be absorbed throughout the bowel; if the disease is in the colon you might want to give olsalazine which is metabolised to two active 5-ASA molecules there.

Good for maintenance of remission in UC.

GOOD FOR UC, NOT THAT GOOD FOR CD.

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20
Q

MoA of Aminosalicylates

A
  • not absorbed well in the SI -> most in ileum, colon or passes through and exits via stool
  • enters cells, is transformed to N-acetyl-5-ASA (via NAT1 - N-acetyl transferase 1) binds to further structures e.g. PPAR-gamma, changes ic gene activation with the effects:

(PPAR gamma translocates to the nucleus after it binds and there is conformational change. -> this change promotes the recruitment of co-activator DRAP -> binds to PPAR gamma and heterodimerisaton with RXR occurs)

 a) decreased NFkB / MAPK which decreases the amount of pro-inflammatory cytokines (incl. TNF-alpha, IL-1beta, IL-6)
 b) decreases COX2 which reduces prostaglandins (PGE2, PGF2) - Transcription modulator

=> ANTI INFLAMMATORY in the GI tract (mainly colon)

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21
Q

Mesalazine vs. Olsalazine

A

Mesalazine does not have to be matabolised, absorption in small bowel and colon

Olsalazine is metabolised in the colon by the colonic flora and therefor is absorbed in the colon.

M is 5-ASA, O is 2 5-ASA linked together.

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22
Q

Aminosalicylates in UC

A
  • Effective at induction and maintenance of remission
  • Combined oral and rectal administration probably more effective than either alone for generalised disease
  • Rectal delivery better for localised disease (proctitis)
  • Probably better than glucortocoids
23
Q

What is better in treatment of ulcerative colitis, glucocorticoids or aminosalicylates?

A

aminosalicylates

24
Q

Aminosalicylates in CD

A
  • Ineffective in inducing remission of CD
  • A very modest amount of evidence for effectiveness in maintenance
  • However, other therapies preferable for maintenance
25
Q

Glucocorticoids in IBD

A
  • Examples: Prednisolone, Fluticasone, budesonide
  • Powerful anti-inflammatory and immunosuppressive drugs
  • Derived from the hormone cortisol
  • Activate intracellular Glucocorticoid Receptors which can then act as positive or negative transcription factors
26
Q

Budesonide

A

= glucocorticoid

- not absorbed, tends to stay in the gut -> fewer side effects -> good for GI disease

27
Q

How do glucocorticoids have their anti-inflammatory actions?

A
  • downregulate IL-1beta and TNF-alpha
  • downregulates T-cell actions
  • downregulates macrophages
28
Q

What are the up and downsides of different glucocorticoid as a treatment of IBD?

A

Prednisolone:

  • better at inducing remission
  • more systemic side effects
  • glucocorticoids have many systemic side effects, some of which can be quite dangerous.

Budesomide:

  • less SE because it is not absorbed and acts pretty much only in the gut
  • less effective as a treatment of IBD
29
Q

Use of Glucocorticoids in IBD

A

Ulcerative colitis

  • Strong clinical evidence that aminosalicylates superior
  • Glucocorticoids not recommended
  • the clinical findings suggest this however, the scientific reasoning behind this is not quite understood.

Crohn’s Disease

  • GCs drugs of choice for inducing remission
  • Budesonide preferred if mild; prednisolone should be given when. more sever because it is more effective.
  • Avoid as maintenance therapy due to side effects
30
Q

Azathioprine

A
  • A pro-drug Activated by gut flora to 6-mercaptopurine
  • Give 6-mercaptopurine directly
  • Purine antagonist
  • interferes with cell repilactoin and DNA synthesis
  • Immunosuppressive
31
Q

What are the effects of Azathioprine on the immune response?

A

It impairs:

  • cell- and antibody-mediated immune responses
  • lymphocyte proliferation
  • mononuclear cell infiltration
  • synthesis of antibodies

It enhances
- T cell apoptosis

32
Q

Azathioprine and CD

A
  • Not recommended for active disease
  • Azathioprine or other immunosuppressants recommended for maintaining remission
  • Glucocorticoid-sparing
  • Slow onset – 3 to 4 months treatment for clinical benefit (which is why you don’t want to give it to induce remission)
    If ineffective move to biological therapies

not for UC

33
Q

What are some unwanted effects of azathioprine?

A
  • Nearly 10% patients have to stop treatment because of side effects
  • Pancreatitis
  • BM suppression
  • Hepatotoxicity
  • Increased risk (~ 4 fold) of lymphoma and skin cancer
34
Q

Strategies of minimising unwanted effects of drugs

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
35
Q

What are the problems with giving allopurinol?

A
  • it inhibits xanthine oxidase which is the enzyme that produces one of the inactive metabolites of 6-MP
  • if this happens, the other metabolites increase in amount
  • this includes increased 6-TGN which has beneficial effects in terms of CD BUT: causes myelosuppression and can cause quite serious blood dyscrasias

Use azathioprine with care if the patient is taking allopurinol.

36
Q

What are some strategies for targeted drug delivery?

A
  • pH dependant coating
  • time-dependant coating
  • osmotic/pressure controlled coating (semipermeable membrane)
  • prodrug conjugates
  • there are now new polymers that combine time and pH dependancy (Potential to give better targeting of drugs to areas of inflammation)
  • nanoparticles packaged in different ways increasingly used.

=> if it is more targeted, you can reduce the overall dose and decrease the side effects.

37
Q

What are the main types of potentially curative therapies for IBD?

A
  • Manipulation of the microbiome
  • Biologic Therapies
    • Anti-TNFa eg Infliximab
    • Many others
38
Q

Manipulation of the microbiome

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. Probiotic therapies
    • Different organisms have different effects so difficult to generalise
    • No evidence for probiotics in CD.
    • Weak evidence for maintenance of remission in UC
  3. Faecal microbiota replacement (FMT) therapies
    - 2 of 3 RCTs showed benefit in UC
    - Unclear if changed microbiome is cause or effect
  4. Antibiotic Treatment – Rifaximin
    - Interferes with bacterial transcription by binding to RNA polymerase
    - Benefit shown in experimental models of IBD
    - May be microbiome modulator
    - Not absorbed from gut
    - Some evidence for sustained remission in moderate CD
    - no evidence for UC
    - Only recommended if complications relating to infection
39
Q

Biologic Therapies

A
  • Approved for use in IBD
  • Anti- TNFa antibodies
  • Example: Infliximab (iv)
  • Other antibodies effective but some have more side-effects
  • New humanised antibodies coming on stream eg Entanacept
40
Q

Infliximab

A
  • anti-TNFalpha AB
  • works on TNF alpha that is free and that is bound to membranes.
  • mops up TNF alpha and stops them acting on the receptors
  • Reduces downstream inflammatory events
  • Binds to membrane associated TNFa
  • Induces cytolysis of cells expressing TNFa
  • Promotes apoptosis of activated T cells
  • Early use better than last resort
  • Combined infliximab and azathioprine therapy recommended rather than monotherapy

SHOULD NOT BE USED AS A FIRST LINE TREATMENT because there are significant side effects.

41
Q

Pharmacokinetics of Infliximab

A
  • Infliximab given intravenously (cannot be given orally because it is an AB)
  • Very long half-life (9.5 days)
  • Most patients relapse after 8 – 12 weeks
  • Therefore repeat infusion every 8 weeks
42
Q

Anti-TNFalpha in IBD

A
  • Used successfully in the treatment of CD (not UC)
  • 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
43
Q

Problems with anti-TNFalpha

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.
44
Q

Adverse effects of TNF-alpha

A
  • 4x - 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 – azothiaprine reduces risk, but raises TB /maligancy risk
45
Q

New targets in IBD treatment

A
  • Integrins (needed for cells to migrate)
  • Interleukins (IL12; IL17;IL23)
  • Interleukin receptors
  • Janus kinase (JAK) cytoplasmic cell signalling
46
Q

Anti-TNFalpha and UC

A
  • in maintenance and induction of mucosal healing there are some benefits of anti-TNF therapy
  • makes us question if UC is Th1 one type Th2
  • we thought it is all Th2 but maybe it is more Th1 type if this drug works.
47
Q

MCQ1: In IBD, budesonide causes fewer unwanted systemic effects than prednisolone because:

a) It can be administered topically
b) It can be co-administered with another drug
c) It has a higher potency at therapeutic doses
d) It has a lower potency at therapeutic doses
e) It is metabolised and inactivated locally

A

a) It can be administered topically
- True but so can other glucocorticoids

b) It can be co-administered with another drug
- True but not unique to budesonide

c) It has a higher potency at therapeutic doses
- Potencies are similar

d) It has a lower potency at therapeutic doses
- Potencies are similar
e) It is metabolised and inactivated locally
- Best answer

=> It is metabolised and inactivated locally

48
Q

MCQ2: The mechanism of action of Azathioprine in IBD:

a) Interferes with purine biosynthesis
b) Is a direct reduction of protein synthesis in the GI tract
c) Is blocked by co-administration with allopurinol
d) Means that it increases side-effects caused by infliximab
e) Needs activation of the drug by metabolism to 5-ASA

A

a) Interferes with purine biosynthesis
True

b) Is direct reduction of protein synthesis in the GI tract
untrue - it will reduce protein synthesis INDIRECTLY

c) Is blocked by co-administration with allopurinol
untrue - allopurinol inhibits metabolism

d) Means that it increases side-effects of infliximab
untrue – it reduces side effects of infliximab

e) Needs pro-drug activation by metabolism to 5-ASA
untrue – it needs activation to 6-mercaptopurine

49
Q

What are the 4 categories where mutations can occur and cause iBD?

A
  • Impaired mucosal defence
  • loss of tolerance
  • epithelial barrier defects
  • diverse mechanisms
50
Q

PPAR RXR complex

A
  • transcriptional regulator
  • formed e.g. after taking 5-ASA (after a couple of steps)
  • controls transcription by binding PPRE ( regulatory PPAR gamma response element)
  • modulated transcription of genes involved in the normal inflammation process.
51
Q

What are the effects of 5-ASA in terms of gene transcription?

A
  • downregulation of NFKB and MAPK
  • this reduces the production of pro-inflammatory cytokines such as TNF-alpha, IL-1beta, IL-6
  • also inhibits COX2 -> decreased prostaglandins (PGE2 and PGF2, involved in inflammation)
52
Q

Balsalaside

A
  • new generation 5-ASA
  • is able to bypass the SI
  • releases a higher concentration of 5-ASA in the colon
53
Q

Guidelines on treating prostitis

A

Mild to moderately active:

  1. 1g 5-ASA suppository 1x/d
  2. add oral ASA (2-3g/day)
  3. switch to or add corticosteroid suppository
  4. oral steroids 40mg

If there is response to any steps you can decrease frequencies and wean off the meds slowly.

Severely active:
1. 40 mg prednisolone daily (weaning over 6-8 weeks to induce remission)

Year 2 - LCRS - Pharmacology (34 decks)

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