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Pharmacology and therapeutics > IBD > Flashcards

IBD Flashcards

1
Q

What are the main forms of IBD

A

Ulcerative Colitis (UC)
Crohn’s Disease (CD)
Distinction incomplete in ~10% patients (Indeterminate Colitis)
300,000 people in the UK

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2
Q

Summarise IBD in Europe

A

Affects children, adolescents and adults
We are only going to consider therapeutic strategies for adults
Incidence is double in Western Europe than eastern- environmental impact important

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3
Q

Describe the 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

Diverse mechanisms, loss of tolerance, epithelial barrier defects and impaired mucosal defence all interact with the environment

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4
Q

What are the environmental risk factors for IBD

A 
Smoking
Medication
Diet
Sleep
Stress
Physical Activty
Air pollution
UV exposure, Vit D
Microbiome
Appendectomy
Heavy Metal

o Obesity – ONLY for CD and not for UC.

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5
Q

Outline the pathogenesis of UC and CD

A

Defective interaction between mucosal immune system and gut flora - infection
10 x more gut bacteria than host cells

Complex interplay between host and microbes

Disrupted innate immunity and impaired clearance

Pro-inflammatory compensatory responses

Physical damage and chronic inflammation

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6
Q

Describe the impact of the microbiome on the pathogenesis of IBD

A

Host genetic factors and environmental factors interact - leading to dysbiosis

Reduced mucus layer

Chronic inflammation

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7
Q

Describe the key features of Chron’s

A

Th1-mediated e.g. IL-1ß, IL-6, IFNg, TNFa, IL-17, IL-23

Florid T cell expansion
Defective T cell apoptosis

All gut layers affected

Can affect any part of G.I

Inflammed areas are patchy

Abscesses/fistulae and fissure are common

surgery not always curative- due to patchy nature

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8
Q

Describe the key features of UC

A

Th2- mediated .g. IL-5, IL-13

Limited clonal expansion
Normal T cell apoptosis

Affects mucosa and submucosa

Starts at rectum and spreads proximally

Inflammed areas are usually continuous

Absecces/fissures and fistulae are not common

surgery therefore curative

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9
Q

Describe the clinical features of IBD

A 
Abdominal pain and crampitng
Diarrhoea, bloody faeces
Mouth ulcers 
Anaemia
Fever
Arthritic pain 
Skin rashes 
Uveitis
Weight loss

can get systemic symptoms, especially with Crohn’s

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10
Q

Summarise the different therapies available for IBD

A

Supportive - fluids, bloods, nutritional support

Symptomatic (active disease and to prevent remission) - glucocorticoids, aminosalicyaltes and immunosuppressives

potentially curative- microbiome manipulation and biologic therapies

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11
Q

Describe the supportive therapies for the acutely sick patient

A

Fluid/electrolyte replacement

	- Blood transfusion/ oral iron 	
	- Nutritional support (malnutrition 	common)
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12
Q

Summarise the classical symptomatic treatments

A

Active disease and prevention of relapse

Aminosalicylates eg Mesalazine
Glucocorticoids eg Prednisolone
- Immunosuppressives eg Azathioprine

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13
Q

What are the aminosalicylates

A

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

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14
Q

Describe the pharmacokinetics of aminosalicylates

A

Mesalazine does not have to be activated any further and is absorbed in the small bowel and colon
Olsalazine must be activated by colonic flora - good if IBD localised to colon- as more will get there

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15
Q

Describe the mechanism of action of aminosalicylates

A

o Inhibition of IL-1, TNF-a and PAF (Platelet Activating Factor).
o Decrease antibody secretion.
o Non-specific cytokine inhibition.
o Reduce cell migration – macrophages.
o Localised inhibition of immune responses.

Binds to PPAR receptos- transcription modulator- down-regulates pro-inflammatory reactions

Inhibits COX-2:
Reducing synthesis of prostaglandins (PGE2 and PGF2)

Inhibits NFkB/MAPK

Reducing synthesis of pro-inflammatory cytokines such as TNF-a, IL-1B and IL-6

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16
Q

Describe the use of aminsalicyclates 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
first line in inducing and maintaining remission with a good evidence base.

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17
Q

Describe the use of the aminosaliclates 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

o Crohn’s disease – non-effective in active disease but may help maintain surgically-induced remission.

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18
Q

What are the glucocorticoids

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

BUDESONIDE- NOT ABSORBED- SAtYS IN GUT- FEWER SIDE EFFECTS

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19
Q

Describe the impact of glucocorticoids in IBD

A

Promotes regulatory effect on dendritic cells, M2 macrophages (which increase regulatory DCs)

Inhibits activity of IL-6, TNF-a, and IL-17

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20
Q

Describe how glucocorticoids work in IBD

A

Glucocorticoids (GCs) are anti-inflammatory drugs that activate intracellular GC receptors. The activated receptors then act as positive transcription factors, increasing the expression of antiinflammatory genes or, more frequently, negative transcription factors, reducing the expression of pro-inflammatory genes.

They act on many cell types and have powerful anti-inflammatory actions including a reduction in the influx and activation of proinflammatory cells and a reduced production of the mediators which cause vasodilation, fluid exudation (swelling), further inflammatory cell recruitment and tissue degradation.

Additionally, GCs are potent immunosuppressive drugs, causing reductions in antigen presentation, cell proliferation and clonal expansion.

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21
Q

What are the important side effects of glucocorticoids

A

Very potent anti-inflammatory and immunosuppressive actions of GCsWhen given systemically, chronic glucocorticoid administration causes many unwanted effects.
The incidence and severity of side effects are closely
related to the dose and duration of GC given.

Unwanted effects of GCs are:

Osteoporosis
Increased risk of Gastric ulceration
Suppression of HPA axis
Type II diabetes
Hypertension
Susceptibility to infection
Skin thinning, bruising and slow wound healing
Muscle wasting and buffalo hump
22
Q

What is the issue with budenoside

A

Budesonide has fewer side effects than other glucocorticoids but it is less effective at inducing remission in CD

23
Q

Describe the use of glucocorticoids in IBD

A

Ulcerative colitis
Strong evidence that aminosalicylates superior
Glucocorticoids not recommended
Crohn’s Disease
GCs drugs of choice for inducing remission
Budesonide preferred if mild
Avoid as maintenance therapy due to side effects

24
Q

How can we minimise the side effects of glucocorticoids in IBD

A

GCs play a key role in the management of CD, so strategies have been developed for minimising their unwanted effects. These strategies include the use of tapered doses, the use of drugs with
a high therapeutic index such as fluticasone, and topical administration (particularly of budesonide which has a high first pass metabolism in the liver and GIT). Because of their unwanted effects, GCs are best used to treat active disease rather than to maintain remission and prevent relapse. Despite their powerful anti-inflammatory actions, they are less effective than aminosalicylates (see below) in the treatment of UC.

25
Q

State three immunosuppressive agents that can be used to treat IBD

A

Azathioprine
Methotrexate
Cyclosporin – only useful in severe UC

26
Q

What is azathioprine

A

A pro-drug Activated by gut flora to 6-mercaptopurine
Give 6-mercaptopurine directly
Purine antagonist (interferes with DNA replication and synthesis)
Immunosuppressive

27
Q

Describe the effect 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
28
Q

Describe the use of azathioprine in Chron’s disease

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
If ineffective move to biological therapies

29
Q

What are the main routes of metabolism of 6MP

A

 Three main routes of metabolism of 6MP:
o HPRT – beneficial but causes myelosuppression.
o TPMT – hepatotoxic metabolites.
o XO – inert metabolites – IDEAL and main pathway.
 However, a drug called allopurinol (treats gout) inhibits CO and so blocks this pathway.

30
Q

Describe the main side effects of azathriprine

A

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

31
Q

Outline the further metabolism of 6-MP

A

Converted to 6-TU inactive by Xanthine oxidase (Allopurinol inhibits)- promoting metabolism down other routes

TMPT converts to 6-MeMp which is hepatotoxic

HGPRT converts to 6-TIMP:
TPMT converts 6-TIMP to 6-MeMPN (inhibiton of de novo purine synthesis)
IMPD, GMPSa nd various kinases convert 6-TIMP to 6-TGN (incorporates into DNA)- beneficial but also causes immunosuppression

32
Q

Summarise the strategies for minimising the 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

33
Q

Describe the strategies for targeting drug delivery b

A

pH dependent polymer coating
Pressure/osmotic controlled coating system (Aqueous environment in lower intestine- water moves in- pushing drug out)

Time dependent polymer coating
Prodrug based conjugates (Olsalazine)

These can reduce systemic toxicity

New complex polymers which combine time and pH

Potential to give better targeting of drugs to areas of inflammation

34
Q

Summarise the potentially curative treatments

A 
	Curative (potentially) treatments:
o	Manipulation of the microbiome.
o	Drugs:
	Anti-TNF-a (e.g. infliximab).
	Anti-a-4-integrins (e.g. natalizumab).
35
Q

Describe EEN as modification of the microbiome

A

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

36
Q

Describe the role of probiotics in manipulating the microbiome

A

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

Npot tailored to individual’s microbiota

37
Q

Describe the role of FMT in manipulating the microbiome

A

. Faecal microbiota replacement (FMT) therapies
- 2 of 3 RCTs showed benefit in UC
- Unclear if changed microbiome is cause or effect
Replace with healthy microbiota to outgrow pathogens

38
Q

Describe how antibiotic treatment can manipulate the microbiome

A
  1. Antibiotic Treatment – Rifaximin
     - Interferes with bacterial transcription 	by binding to RNA polymerase 
 - Benefit shown in experimental 	models of IBD
39
Q

Describe the experimental data associated with Rifaximin

A

Rifaximin reduces inflammatory mediator mRNA in experimental colitis (reduces expression of IL-10, IL-6 and IL-1b)

DSS = dextran sulphate sodium = induces experimental IBD

May be microbiome modulator
- Not absorbed from gut
-Some evidence for sustained remission in moderate CD
- Only recommended if complications relating to infection (i.e abscesses or fistulae)
may be useful in UC

40
Q

Summarise the 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

41
Q

Give two examples of anti-TNFa antibodies

A

Infliximab (IV)

Adalimumab (SC)

42
Q

Describe the mechanism of action of anti-TNFa antibodies

A

Anti- TNFa reduces activation of TNF a receptors in the gut
Reduces downstream inflammatory events
Binds to membrane associated TNFa
Induces cytolysis of cells expressing TNFa
Promotes apoptosis of activated T cells

Bounds to soluble TNF and bound TNF

43
Q

Describe the pharmacokinetics of infliximab

A 
Infliximab given intravenously
Very long half-life (9.5 days)
Most patients relapse after 8 – 12 weeks
Therefore repeat infusion every 8 weeks
Can't take proteins orally
44
Q

Summarise the use of anti-TNFa antibodies in IBD

A

 Anti-TNF-Alpha Antibodies:
o CD – used successfully, 60% responsive within 6 weeks, potentially curative.
o UC – some evidence of effectiveness (but UC is not TNF-a mediated, it is mainly IL mediated).

Used successfully in the treatment of CD
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

UC may be more Th1

45
Q

Describe the problems with anti-TNFa antibodies

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- antibodies to the antibody

Attempts being made to optimise dosing regimens (combine with azathioprine)

46
Q

Describe the adverse effects of anti-TNFa antibodies

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

47
Q

Summarise the use of infliximabs

A

Early use better than last resort

Combined infliximab and azathioprine therapy recommended rather than monotherapy

48
Q

Describe the SONIC trial findings

A

 SONIC trial findings – a study on infliximab:
o Early use of infliximab in refractory disease is better than using it as a last resort.
o CRP levels and endoscopy might allow identification of patients most likely to benefit.
o Greater risk of infection and lymphoma.

49
Q

Describe some potential new targets

A

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

50
Q

Explain the rationale for the new targets

A

 Alpha-4 Integrin – cell adhesion molecule.
 IL-13 – particularly in UC.
 Janus kinases 1, 2, 3 – block signalling by IL-2, 4, 9, 15, 21 (lymphocyte activation and function) and IL-6 and INF-gamma (pro-inflammatory) – good in UC.

51
Q

Summarise the biologic therapies

A

These drugs constitute the first generation of potentially curative therapies for the treatment of CD. Infliximab (anti-TNFα) is demonstrating some success in patients with previously intractable and steroid-dependent disease, although relapse is still common. The safety profile is general good, but some subjects can develop very serious side effects which can be severe. Because Crohn’s Disease (unlike UC) is a Th1-mediated autoimmune disease, TNFα plays a key role in its pathogenesis, so anti- TNFα can be of therapeutic benefit. It reduces activation of TNFα receptors in the gut and hence, other inflammatory responses downstream of TNFα such as the production of other cytokines and the infiltration and activation of leukocytes are also reduced.

Co-administration with immunomodulators reduces immunogenic side-effects, but increases the risk of serious infection (e.g. TB) and malignancy. Thus the risk/benefit equation must be
considered for each patient individually.

Infliximab and other drugs like it are likely to be very important for the future treatment of autoimmune disorders

52
Q

Summarise the aminosalicylates

A

Aminosalicylates have fewer anti-inflammatory actions than GCs and no immunosuppressive effects and because of this, they are safer to use chronically for the maintenance of remission. They reduce the recruitment of inflammatory leukocytes and reduce the production of a number of inflammatory mediators. Aminosalicylates in current clinical use include Sulfasalazine, Mesalazine, Olsalazine.

The first to be used was sulfasalazine, but this has unwanted side effects due to its sulfapyridine moiety. These can be avoided by administering the therapeutically active component 5-aminosalicylic acid (ASA) also called mesalazine on its own. A newer drug, olsalazine, consists of 2 linked 5-ASA moieties.

Except for 5-ASA given alone, all these derivatives are activated by the gut flora.

It is therefore possible to control the site of absorption by modifying the route of drug administration and the exact formulation of the drug. You should know about the sorts of modifications which can be made to target the drugs to different parts of the GIT.

Aminosalicylates are the first line treatment for ulcerative colitis.

Pharmacology and therapeutics (30 decks)

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