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Year 2 - Pharm Lectures 11+ > IBD > Flashcards

IBD Flashcards

1
Q

2 major forms of IBD?

A

Ulcerative Colitis (UC)

Crohn’s Disease (CD)
• more studied of the 2

Distinction incomplete in ~10% of pop.
• Indeterminate Colitis

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2
Q

Risk factors for IBD?

A

Genetic Predisposition
• in 201 loci

Environmental factors
• smoking (CD especially)
• diet/obesity
• gut microbiome

Obesity
• ONLY for CD (NOT for UC)

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3
Q

Pathogenesis of IBD?

A

Defective interactions between the mucosal I.S & the gut flora
• leads to disrupted innate immunity –> uncontrolled inflammation –> physical damage

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4
Q

UC?

AI disease
Gut layers affected
Regions of gut affected
Inflamed areas are:
Abcesses/fissures/fistulae
Surgery
A

Th2-mediated
• limited clonal expansion
• normal T-cell apoptosis

Dependant on IL-5 & IL-13 cytokines

Affects mucosa and submucosa

Starts in rectum, spreads proximally

Inflamed areas are usually: CONTINOUS

Abcesses/fissures etc: NOT COMMON

Surgery can be curative

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5
Q

CD?

AI disease
Gut layers affected
Regions of gut affected
Inflamed areas are:
Abcesses/fissures/fistulae
Surgery
A

Th1-mediated
• worst inflammatory response
• florid T-cell expansion
• defective T-cell apoptosis

Dependant on TNF-a cytokine

Penetrates all through gut wall
• aka. ALL LAYERS affected

Affects any point of the GI tract

Causes patchy (not continuous) inflammation
 • hard to cure with surgery and often reoccurs

Abscesses, fissures and fistula MORE COMMON

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6
Q

Clinical features of IBD?

A

Can be systemic as well as local

	Right iliac fossa pain.
	Skin rash.
	Diarrhoea, blood, mucus.
	Weight loss.
	Arthritis, arthralgia.
	Abdominal pain.
	Anaemia.
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7
Q

Summary of the therapies available for IBD - for adults only

A

SUPPORTIVE therapies:
o Fluid/electrolyte replacement
o Blood transfusion or oral iron
o Nutritional support – as malnutrition is common

Classic SYMPTOMATIC treatments – we can’t cure these diseases outright:
o Glucocorticoids – e.g. prednisolone
o Aminosalicylates – e.g. mesalazine
o Immunosuppressives – e.g. azathioprine

CURATIVE (potentially) treatments:
 o Manipulation of the microbiome
 o Drugs:
   Anti-TNF-a (e.g. infliximab)
   Anti-a-4-integrins (e.g. natalizumab)
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8
Q

Describe the use of Aminosalicylates for the treatment of UC & CD

•

A

Ulcerative colitis
– first line in inducing and maintaining remission with a good evidence base

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

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9
Q

Example Aminosalicylates drugs?

A

Mesalazine

Olsalazine

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10
Q

General information regarding Aminosalicylates & its drugs?

A

Mesalazine (5-aminosalicyclic acid / 5-ASA)
• Olsalazine (2 linked 5-ASA molecules)

These are anti-inflammatory drugs.

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11
Q

MoA 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

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12
Q

Explain the pharmacokinetics of 5-ASA and its derivatives

A

Mesalazine – does NOT need to be metabolised & is ABOSRBED by small bowel and colon

  • Good at maintaining remission in UC.
  • Topical 5-ASA is better than topical steroids at inducing UC remission
  • Combined topical 5-ASA and oral steroids better at inducing remission than oral 5-ASA alone

Olsalazine – metabolised by gut flora and absorbed by the colon

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13
Q

Describe the treatment of Glucocorticoids for UC & CD

A

Ulcerative colitis
– use is in decline
– can be used topically or via IV
– 5-ASA seems to be superior

Crohn’s disease
– drug of choice for inducing remission
– SEs likely if used to maintain remission

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14
Q

General information surrounding Glucocorticoids and its use?

A

o Powerful anti-inflammatories
o Powerful Immunosuppressives

o Activate intra-cellular GC receptors –> ±transcription factors

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15
Q

Example glucocorticoid drugs?

A

Prednisolone

Fluticasone

Budesonide

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16
Q

Explain the pharmacokinetics of glucocorticoids

A

Glucocorticoids have many long-term use side effects SO methods for reducing SEs:

 Administer topically.
 Use a low-dose in combination with another drug (steroid-sparing agent)
 Use an oral/topical drug with HIGH first-pass metabolism (e.g. Budesonide), so little escapes systemically –> Budesonide has fewer SEs than Prednisolone

  • Oral GCs are better than Budesonide at inducing remission in ACTIVE Crohn’s disease.
  • Budesonide is a better than placebo at preventing CD relapse
17
Q

Example Imuunosuppresive drugs that are used?

A

Azathioprine

Methotrexate

Cyclosporine

18
Q

General information about Azathioprine and its use?

A

CD
• used to maintain remission – superior to placebo & Budesonide in CD

UC
• useful for maintaining remission in SOME patients

o Considered a “Steroid-sparing agent”
o Slow onset of action
– 3-4 months’ treatment is required before clinical benefits are seen

19
Q

General information about Methotreaxate and its use?

A

Efficacy in SOME IBD patients.
o A folate antagonist.
o Reduces the synthesis of thymidine and other purines.
o NOT widely used due to significant side effects (in over 40% of patients).

20
Q

General information about Cyclosporine?

A

Used in severe UC

21
Q

MoA of Azathioprine

A

Aza is a pro-drug activated (in vivo) by the gut flora to 6-mercaptopurine (6-MP)
• can give 6MP DIRECTLY

6MP is a purine antagonist - thus interferes with:
• DNA synthesis & cell replication

22
Q

What does Azathioprine impair?

A
  • Humoral and innate immune responses
  • Lymphocyte proliferation
  • Mononuclear cell infiltration
  • Synthesis of antibodies
23
Q

What does Azathioprine enhance?

A

• T-cell apoptosis

24
Q

Unwanted effects associated with Azathioprine?

A

~10% patients experience side effects.

Associated with:
	Pancreatitis
	Bone marrow suppression.
	Hepatotoxicity.
	x4 risk increase of lymphoma and skin cancer.
25
Q

There are 3 main routes of metabolism of Azathioprine - what are they and explain

A

Azathioprine is activated to 6-MP which then:

  1. HPRT
    • beneficial BUT causes myelosuppression
  2. TPMT
    • produces hepatotoxic metabolites
  3. XO
    • produces inert metabolites - IDEAL & MAIN pathway
    BUT
    • a drug called ALLOPURINOL (treats gout) inhibits Xanthine Oxidase = blocks this pathway
26
Q

One potential curative therapy is microbiome manipulation - explain the different kinds that can be used

A

Nutrition-based therapies:
• CD – no evidence for probiotics.
• UC – evidence for probiotics in the induction and maintenance of remission

Faecal microbiota replacement (FMT):
• Insufficient evidence for FMT – 1 study showing remission/cure in UC

Antibiotic treatment (Rifaximin):
• CD – induces and sustains remission in moderate cases
• UC – may be beneficial
• Interferes with bacterial transcription by binding to RNA polymerase – reduces mRNA coding by inflammatory mediators.

27
Q

What is the drug used as the Antibiotic Treatment for microbiome manipulation?

A

Rifaximin

28
Q

What biological therapies are there for the curative treatment of IBD?

A

Approved for use in IBD:

• Anti TNF-alpha Abs

  • Infliximab (IV)
  • Adalimumab (SC)

• Other Abs are also effective BUT have more SEs

29
Q

Explain the use of Anti-TNF-alpha Abs in both UC & CD

A

CD
– used successfully
– 60% responsive within 6 weeks
– potentially curative

UC
– some evidence of effectiveness (but UC is NOT TNF-a mediated, it is mainly IL mediated)
 Infliximab – binds to soluble TNF-a and receptor bound TNF-a –> it can strip away already TNF-a bound onto cells

30
Q

Drugs used as Anti-TNF-a Abs biological therapy?

A

Infliximab - IV

Adalimumab - SC

31
Q

Explain the MoA of the Anti-TNF-a Abs biological therapy

A

Reduces activation of TNF-a receptors in the gut

As TNF-a activates other cytokines, TNF-a inactivation:
• downregulates other cytokines
• infiltration & activation of leukocytes

Binds to membrane associated TNF-a as well as soluble TNF-a
 Induces CYTOLYSIS of cells expressing TNF-a
 Promotes APOPTOSIS of activated T-cells

32
Q

Pharmacokinetics of Anti-TNF-a Abs?

A

o Very long T1/2 – 9.5 days

o Benefits last for 30 weeks after infusion
o Patients relapse after 8-12 weeks (repeat infusion every 8 weeks)

33
Q

Problems associated with Anti-TNF-a Abs?

A

~50% of patients lose response to drugs after 3 years due to:
• increased metabolism (i.e. drug clearance)
&
• production of anti-drug ABs

34
Q

Why do adverse effects from Anti-TNF-a Abs arise?

A

Due to consequences of knocking out KEY CYTOKINES in the INFLAMMATORY CASCADE

35
Q

What are the adverse effects of Anti-TNF-a Abs?

A

4-5x increase incidence of TB and other infections
– and risk of reactivating dormant TB

Increased risk of septicaemia
– downregulates inflammation

Worsening of heart failure

Increased risk of demyelinating disease and malignancy

Can be immunogenic
– Azathioprine reduces risk but raises TB/malignancy risk

36
Q

Explain the SONIC trial

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

37
Q

What are other possible targets of biological therapies?

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

38
Q

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

E

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

39
Q

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

A. Interferes with purine biosynthesis
True

B. Is direct reduction of protein synthesis in the GI tract
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

Year 2 - Pharm Lectures 11+ (23 decks)

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