IBD (Chron's and colitis)

Question 1

What is the difference between the location affected in UC and CD?

Answer 1

• Chrons:
  Any part of the GI tract from mouth to rectum can be affected
  Inflammation extends all laters of the gut wall
  inflammation is patchy

Collitis:
Colon and rectum affected only
only affects mucosa and submucosa
Inflammation is diffuse in distribution- starts at rectum and works around colon- not patchy

Question 2

Which is more common?

Answer 2

UC is 2 x more common that CD

Question 3

What is the impact of smoking on uc and cd?

Answer 3

Is thought to prevent the onset of ulcerative colitis
but worsens the clinical course of both diseases

Question 4

What are the symptoms of IBD?

Answer 4

BOTH:
diarrhoea
fever
abdo pain
n+V (More common in CD)
malaise
weight loss (more common in cd)
malabsorption

CD:
Tends to be more disabling
pain in lower right quadrant
anaemia
palpable masses
abcesses
fistulas
gut perforation

UC:
Diarrhoea- blood, mucus
abdo pain
constipation

Question 5

What are the possible complications of IBD?

Answer 5

Inflammation can spill into other areas:
Joints and bones- arthritis like symptoms

Skin- Erthema nodosum- tender, hot, red nodules
pyoderma gangrenous- pustule –> ulcer

Eye- Episcleritis- intense burning and itching

Liver- sclerosing cholangitis- chronic inflammation of billiard tree
narrowing of bile duct, gall bladder = sclerosis and scarring

Question 6

What is cytomegalovirus and how is it treated ?

Answer 6

A virus associated with refractory disease

IV ganciclovir –> oral valganciclovir

Question 7

15% of IBD patients have steroid dependence, what should be co-prescribed with steroids?

Answer 7

30-40% of IBD patents have osteopenia and 15% osteoporosis
- All patient on steroids should have:
800-1000mg calcium and 800 IU Vitamin D daily

Question 8

What doses of calcium and vitamin D should be prescribed in IBD patients and how should this be monitored?

Answer 8

800-1000mg calcium per day
800 IU vitamin D
- should be monitored, if have a low risk = re-check in 3-5 years,
if high:
Consider treatment with a bisphosphonate e.g. aledronate, risedronate

Question 9

If patients are found to have high risk of calcium or vitamin D deficiency after calcium and vitamin D supplements what is the next treatment?

Answer 9

Bisphosphonates e.g. aledronate, risedronate

Question 10

What deficiencies are common in IBD patients?

Answer 10

• Calcium and vitamin D- potassium and vit D
• Magnesium- can ove oral or IV (caution as oral can worsen diarrhoea)
• Potassium e.g. give sand K
• Iron- 1/3 have iron-deficiency anaemia

Question 11

How can iron be supplemented in iron deficiencies in IBD?

Answer 11

• In inactive IBD- can give oral iron supplements - 100mg a day
• If active - give IV iron e.g. ferric carboxymaltose

Question 12

Can NSAIDs be taken by patients with IBD?

Answer 12

Short-term is potentially safe but should be avoided as much as possible as can cause increase in disease activity and relapse

Question 13

Can IBD patients be given opioids for pain relief?

Answer 13

Shouldn’t as they can cause constipation
- have poor IBD outcomes and risk of addiction

Question 14

Can IBD patients have vaccinations?

Answer 14

It’s recommended you have the flu jab every year and the one-off pneumococcal vaccination.

But avoid having any live vaccines

Question 15

Examples of aminosalicyclates used in IBD

Answer 15

Mesalazine
sulfasalazine

Question 16

How does sulfasalazine work in IBD?

Answer 16

Sulfasalazine contains Mesalazine (active drug) bound to sulfapyridine (inert carrier) via an azo bond.
- The azo bond prevents drug absorption in the upper gi tract as azoreductase is needed to break the azo bond which is produced by anaerobic bacteria in the colon.

• Caution if patient is sensitive to sulfapyridine or other sulphonamide antibiotics

Question 17

What monitoring is required for patients on aminosalicylates?

Answer 17

FBC- every other week for 3 months, then monthly for 3 months, then every 3 months

LFTs- every other week for 3 months, then monthly for 3 months, then every 3 months

Renal function- creatinine, eGFR- monthly for 3 months, then as indicates

Instruct to patients signs of myelosuppression and hepatotoxicity- sore throat, fever, malaise, jaundice

Question 18

What may sulfasalazine do to urine?

Answer 18

May colour urine
May also make contact lenses go yellow

Question 19

What are the different formulation mechanisms that change the release of Mesalazine in the GIT?

Answer 19

ENTERIC COATING:
- Adds a specific coating that is released at a specific pH to prevent early degradation in the stomach
e.g. Eudragit S - Dissolves at pH >7 e.g. salofalk
Eudragit L - Dissolved at pH >6 e.g. octave
jejunum= pH 6-7 and ileum and colon = 7+
issue- pH can be varied in IBD patients

TIME-DEPENDENT:
-Contains microspheres of mesalazine encapsulated in an ethyl cellulose semi-permeable membrane
- This makes it time and moisture dependent (not ph)
Releases slowly throughout the GIT- stomach, duodenum, rectum

MULTI-MATRIX MESALAZINE-
mesalazine incorporated into lipophilic matrix and is enteric ally coated
Dissolution at pH >7
- Matrix swells = gel forms = slow diffusion in the terminal ileum and colon

brands can’t be interchanged

Question 20

What tests need to be done prior to initiation of thiopurines (e.g. mercaptopurine, azathioprine)?

Answer 20

FBC
LFT
U&E
Vaccinate- flu and pneumococcal
up to date cervical screening
Check TPMT - Thiopurine methyl transferase- enzyme needed to breakdown mercaptopurine

Question 21

What would you not do if a patient has a low TPMT level?

Answer 21

TPMT = Thiopurine methyl transferase- enzyme needed to breakdown mercaptopurine
If low = AVOID thiopurines e.g. mercaptopurine and azathioprine

Question 22

What is the important drug interaction with Allopurinol?

Answer 22

Allopurinol and Azathioprine
If they must be taken together- decrease dose of Azathioprine to 1/4 of its usual dose

• Allopurinol interferes with the metabolism of azathioprine, increasing plasma levels of 6-mercaptopurine which may result in potentially fatal blood dyscrasias

Question 23

What is the MOA of glucocorticoids in treating IBD?

Answer 23

• Glucocorticoids enter target cells and bind to the intracellular glucocorticoid receptor (GR) in the cytoplasm = activated
• This allows the formation of a homodimer of two activated GRs
• This homodimer is transported to the nucleus where it inhibits promoter regions of genes such as NFKB and AP-1 - These are potent transcription factors for many pro-inflammatory cytokines and adhesion genes.

Question 24

What is the MOA of Azathioprine?

Answer 24

Inhibits de novo synthesis of purine nucleotides- interferes with DNA and RNA synthesis

LOOK AT DIAGRAM IN BOOK

Azathioprine
I
I
V
6-MP
I
I
V
TIMP
I I
I V
V 6TGN- is incorporated into DNA
6- McMpN
- Inhibits purine synthesis

Question 25

How do aminosalicyclates work?

Answer 25

Works similar to NSAIDs- inhibit Cyclooxygenase and therefore decreasing prostaglandin synthesis and suppressing production of pro-inflammatory cytokines

• Also impacts cox-independent pathway:
  Decrease neutrophil chemotaxis to sites of inflammation
  Inhibit survival of immune cells through NFKB signalling
• TNF-mediated effects on epithelial proliferation

LOOK INTO BETTER EXPLANATION

Question 26

How does Ciclosporin work?

Answer 26

Modulates pro-inflammatory cytokine production and t-cell survival.

Antigen binds to T-helper cells
= Increase in intracellular Ca2+ ions
= Stimulation of phosphatase and calcineurin

Ciclosporin moa:
- Ciclosporin binds to cyclophilin
- Ciclosporin is a competitive inhibitor of calcineurin and calmodulin-dependent phosphatase
- Calciuneurin normally acts in opposition to protein kinases involved in signal transduction
- ciclosporin inhibits translocation of NF-AT transcription factor and decreases transcription of cytokine genes for:
IL-2, 3,4
TNF-A
CD3OL
GM-CSF
IFN-Y
look at better explanation

Question 27

How does methotrexate work?

Answer 27

Folates are actively taken into cells and are essential for synthesis of purine nucleotides and thymidylate
- Dihydrofolate reductase is involved in thymidylate synthesis- transforms inactive form to active form- dihydrofolate then tetrahydrofolate
- This produces an essential cofactor for transforming DUMP to DTMP required for synthesis of DNA and purines

Methotrexate inhibits dihydrofolate reductase= inhibits purine synthesis

Question 28

How do anti-TNF therapies work?

Answer 28

TNF is elevated in the serum of IBD patients in correspondence with the degree of mucosal inflammation.
e.g. Inflkiximab, golimumab, adalimumab
- Human monoclonal antibodies bind to TNF- prevent the bonding of TNF to its receptors = inhibit biologic activity of TNF
Biologic activity of TNF:
- Activate macrophages to produce proinflammaotry cytokines
- Regulates t-cell apoptosis
- Causes panted cell death
- MMP induced tissue destruction

Question 29

How do t-cell homing and retention therapies work?

Answer 29

in IBD activates t-cells migrate to the gut cells and accumulate and secrete inflammatory cytokines e.g. Il-6, Il-23 and TNF= un-resolving chronic inflammation

• 𝛼4B7 is a cell surface integrin that is specific to the gut and binds to e-cadherin on epithelial cells causing t-cells to be retained in the gut
• blocking t-cell retention and homing to the gut is a potential therapeutic target for IBD

e.g. vendolizumab- blocks 𝛼4B7 homing of t-cells to gut

Ustekinumab- monoclonal antibody hat targets the p40 subunit of il-12 and il-23- these are involved in the activating cascade of inflammatory mediators responsible for IBD pathogenesis. Inhibiton of IL-12 and 23 surpasses Th1 and Th17 cell lineage of cytokines and chemokine present in IBD

Janus kinase inhibitors e.g. Tofactinib, Filgotinib
Suppress pro-inflammatory responses mediated by cytokine receptors e.g. IL-10 and 12

Question 30

What are the future and emerging therapies for use in IBD?

Answer 30

• Epithelial barrier function is impaired in IBD= Contact of lamina propria immune cells with bacteria = inflammation and ulceration

Emerging therapeutic targets:
Restoring mucous layer
Restoring microbial composition

Fecal microbial transfer (FMT):
Transfer of stool from a healthy person into the GI tract of an IBD patient- restoring essential components of microbiome that could revert inflammation

Probiotics e.g. E. coli Nissle
thought to have similar anti-inflammatory effects to aminoslalicyclates - strengthen tight junctions between epithelial cells = increase barrier function

Phosphatidylcholine:
Is an essential protective component of colonic mucus - in UC this content is low = decreased barrier function = potential drug target?