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LCRS Pharma > Pharmacology of IBD > Flashcards

Pharmacology of IBD Flashcards

1
Q

what are the two major forms of IBD?

A

o Ulcerative colitis.
o Crohn’s disease
– most studied of the two as it is the worse one

when there is a fine boundary–> intermediate colitis

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2
Q

what are the risk factors of IBD?

A 
o Genetic predisposition
 – in 163 loci.
o Environmental factors 
– smoking (CD especially), diet/obesity, gut microbiome.
o Obesity
 – ONLY for CD and not for UC.
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3
Q

what is the main pathogenesis of IBD?

A

defective interactions between the mucosal immune system and the gut flora.
disrupted innate immunity
uncontrolled inflammation and therefore physical damage

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4
Q

how is the CD autoimmune disease mediated?

A

Th1 giving a worse inflammatory response
Dependant on TNF-a cytokine.

UC is Th2 mediated

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5
Q

what mediates the UC autoimmune disease?

A

Th2

Dependant on IL-5 & IL-13 cytokines.

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6
Q

how does CD and UC differ in layers of the gut they affect?

A

CD affects all layers of the gut

UC affects the mucosa/submucosa

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7
Q

how does the inflamed area differ in CD and UC?

are abscesses found in them?

A

CD consists of patchy areas of inflammation with abscesses being common. This makes surgical removal very difficult (can then reoccur)

UC consists of continuous areas of inflammation where abscesses are not common and therefore easier to cure by surgery

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8
Q

what are the clinical features of IBD? how are they categorised?

A

systemic and local

	Right iliac fossa pain.
	Skin rash.
	Diarrhoea, blood, mucus.
	Weight loss.
	Arthritis, arthralgia.
	Abdominal pain.
	Anaemia.
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9
Q

what are the different therapies available for different stages of IBD?

A

1- supportive (acute cases)
2- classic symptomatic treatments (not curing the disease; at active state and prevention of remission)
3- (potentially) curative

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10
Q

what are the 3 groups of drugs involved in classic symptomatic treatment?

A

o Glucocorticoids – e.g. prednisolone.
o Aminosalicylates – e.g. mesalazine.
o Immunosuppressives – e.g. azathioprine.

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11
Q

what is provided in supportive therapy in acute cases?

A

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

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12
Q

what are the treatment options in the potentially curative treatment?

A 
o	Manipulation of the microbiome.
o	Drugs
 - Anti-TNF-alpha  
(e.g. infliximab).
- Anti-a-4-integrins 
(e.g. natalizumab)
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13
Q

what IBD is aminosalicylates preferred in?

A

Ulcerative colitis – first line in inducing and maintaining remission with a good evidence base. Given oraly and/or rectally (disease at rectum)

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

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14
Q

what is mesalazine?

A

5-aminosalicyclic acid / 5-ASA

e.g. Olsalazine (2 linked 5-ASA molecules)

an anti-inflammatory drug

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15
Q

what is the mechanism of action of mesalazine?

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.

nb PAF is for platelet aggregation, inflammatory and allergy

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16
Q

where is mesalazine absorbed?

A

does not need to be metabolised and is absorbed by small bowel and colon

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17
Q

what effect does mesalazine have in UC?

which form of mesalazine is ideal for this function ?

A
  • maintaining remission in UC
  • Topical 5-ASA is better than topical steroids in
  • Combined topical 5-ASA and oral steroids better at inducing remission than oral 5-ASA alone
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18
Q

where is olsalazine absorbed?

A

metabolised by gut flora and absorbed by the colon

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19
Q

what are the glucocorticoids that can be used in symptomatic treatment?

A

Prednisolone
Fluticasone
Budesonide

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20
Q

which IBD is glucocorticoid use preferred in?

A

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

Ulcerative colitis (not recommended)
– use is in decline, can be used topically or via IV.
5-ASA seems to be superior.

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21
Q

what action do glucocorticoids have in treatment?

A

Powerful anti-inflammatory drug and immunosuppressives

Activate intra-cellular GC receptors to regulate transcription factors.

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22
Q

what is the problem with long term use of glucocorticoids?

A

long-term use side effects: Cushing-like symptoms

  • osteoporosis (fragile bones),
  • hypertension (high blood pressure),
  • diabetes,
  • weight gain,
  • increased vulnerability to infection,
  • cataracts and glaucoma (eye disorders),
  • thinning of the skin,
  • bruising easily
23
Q

how should glucocorticoids be administered to limit its negative effects?

A
  • Administer topically.
  • Use a low-dose in combination with another drug (steroid-sparing agent)
  • Use an oral/topical drug with HIGH first-pass metabolism so little can escape systemically
24
Q

which glucocorticoid option has high first pass metabolism and therefore a preferable glucocorticoid to use?

A

Budesonide (for mild cases)

has fewer SEs than Prednisolone as it stays in the gut and does not escape systemically

25
Q

which form of glucocorticoid are better than Budesonide at inducing remission in active Crohn’s disease?

A

oral GCs

26
Q

what are the immunosuppressives used in symptomatic treatment of IBD?

A

Azathioprine
Methotrexate
Cyclosporine

27
Q

how do CD and UC differ in the regions of the GIT they affect?

A

CD affects any part of the GIT

UC affects the rectum spreading proximally

28
Q

in which IBD can azathioprine be used?

A

in both CD and UC

o CD
- used to maintain remission
- superior to placebo & budesonide in CD.
o UC
- useful for maintaining remission in SOME patients.

29
Q

what type of drug is azathioprine? when can its effects be seen?

A

Immunosuppressive “steroid sparing” agent

Slow onset of action therefore 3-4 months’ treatment is required before clinical benefits are seen.

30
Q

how is azathioprine activated and what action does it have?

A

prodrug activated by gut flora into 6-mercaptopurine (6-MP)
[6-MP could be given directly]

this is a purine antagonist that interferes with DNA synthesis and cell replication

31
Q

what is methotrexate? why is it not used as much any more?

A

immunosuppressive

  • folate antagonist
  • reduces synthesis of thymidine and other purines
  • efficacy in some IBD patients
  • not widely used due to significant side effects
32
Q

in what IBD is cyclosporine used in?

A

UC

33
Q

what are the effects of azathioprine?

A

Impairs:

  • humoral and innate immune responses
  • lymphocyte proliferation
  • mononuclear cell infiltration - synthesis of antibodies

promotes:
- T cell apoptosis

34
Q

what are the unwanted effects of azathioprine?

A

some metabolites have unwanted effects:

  • Bone marrow suppression (6-TGN is myelosuppressive)
  • Hepatotoxicity (6-MeMP)
  • x4 risk increase of lymphoma and skin cancer
  • Pancreatitis
35
Q

what are the 3 metabolism routes of 6-MP?

A

o HPRT – beneficial but causes myelosuppression.

o TPMT – hepatotoxic metabolites.

o XO – inert metabolites (IDEAL and MAIN pathway)
–> allopurinol (treats gout) inhibits XO and so blocks this pathway therefore don’t coadminister

36
Q

what is the preferred route of 6-MP metabolite metabolism?

A

Xanthine Oxidase

produces inert metabolites

37
Q

what are the 3 options that induce microbiome manipulation?

A

 Nutrition-based therapies i.e. probiotics

 Faecal microbiota replacement (FMT)
- insufficient evidence for FMT, it is not known whether change in microbiota is an effect or cause

 Antibiotic treatment (Rifaximin)

38
Q

which IBD is nutritional based therapy preferred in?

A

o UC
– evidence for probiotics in the induction and maintenance of remission, people respond differently

o CD
– no evidence for probiotics

39
Q

which IBD is antibiotic treatment preferred in?

A

o CD
– induces and sustains remission in moderate cases

o UC
– may be beneficial

40
Q

what effect do antibiotics have?

mechanism of action

A

e.g. rifixamin
Interferes with bacterial transcription by binding to RNA polymerase
– reduces mRNA coding by inflammatory mediators.

41
Q

how can delivery of a drug be altered?

A
  • pH dependent
  • time dependent polymer
  • osmotic pressure control using push layer that sweeps and pushes drug out
  • prodrug based conjugate
42
Q

what is nutritional therapy?

A

a liquid diet that rests the mucosa so the flora can recover

hard to maintain in adults (unpalatable)

43
Q

what are the Anti-TNF alpha drugs that can be used?

A

Infliximab (IV)
Adalimumab (SC).

these are monoclonal antibodies
these have fewer side effects

44
Q

which IBD are anti-TNF-alpha antibodies preferred in?

A

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)

45
Q

how does Infliximab affect TNF Alpha?

A
  • binds to soluble TNF-a and receptor bound TNF-a
  • it can strip away TNF-a bound onto cells
  • reduces activation of TNF-a receptors in the gut
46
Q

why is anti TNF alpha not every effective in UC?

A

UC is not mediated by TNF alpha but rather by interleukins

UC is Th2 mediated i.e used IL
CD is Th1 mediated i.e. TNF a

47
Q

what is the effect of TNF-alpha inactivation? what overall effects does this have?

A

As TNF-a activates other cytokines, TNF-a inactivation downregulates other cytokines, and infiltration and activation of leukocytes.

  • Induces cytolysis of cells expressing TNF-a.
  • Promotes apoptosis of activated T-cells.
48
Q

what are the pharmacokinetic details of the anti-TNF-a drugs?

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).

49
Q

what is the problem with use of anti-TNF-a drugs over time?

A

patients lose response to drugs after 3 years due to increased metabolism & anti-drug ABs that have been created

50
Q

what is the root to all the adverse effects of biological therapies?

what are the adverse effects?

A

due to consequences of knocking out the key cytokine inflammatory cascades:

o 4-5x increase incidence of TB and other infections
– and risk of reactivating dormant TB.
o Increased risk of septicaemia
– downregulates inflammation.
o Worsening of heart failure.
o Increased risk of demyelinating disease and malignancy.
o Can be immunogenic
– Azathioprine reduces risk but raises TB/malignancy risk.

51
Q

when should infliximab be used?

A

Early use of infliximab in refractory disease is better than using it as a last resort

These patients at high risk should be identified with endoscopy and CRP levels

52
Q

what are some other targets that potential drugs can target?

A

 Alpha-4 Integrin
– cell adhesion molecule.

 IL-13
– particularly in UC as its Th2 mediated

 Janus kinases 1, 2, 3 
– block signalling by IL-2, 4, 9, 15, 21 
(lymphocyte activation and function) 
- block signalling by IL-6 and INF-gamma
(pro-inflammatory) 
– good in UC as its Th2 mediated
53
Q

what therapies can be used for CD?

A
  • glucocorticoids
  • azathioprine
  • antibiotics
  • Anti-TNF-a drugs

NOT
- aminosalicyclates etc

54
Q

what therapies can be used in UC?

A
  • aminosalicylates
  • azathioprine
  • nutritional based therapies

LCRS Pharma (32 decks)

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