IBD (Chron's and colitis) Flashcards
What is the difference between the location affected in UC and CD?
- 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
Which is more common?
UC is 2 x more common that CD
What is the impact of smoking on uc and cd?
Is thought to prevent the onset of ulcerative colitis
but worsens the clinical course of both diseases
What are the symptoms of IBD?
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
What are the possible complications of IBD?
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
What is cytomegalovirus and how is it treated ?
A virus associated with refractory disease
IV ganciclovir –> oral valganciclovir
15% of IBD patients have steroid dependence, what should be co-prescribed with steroids?
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
What doses of calcium and vitamin D should be prescribed in IBD patients and how should this be monitored?
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
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?
Bisphosphonates e.g. aledronate, risedronate
What deficiencies are common in IBD patients?
- 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
How can iron be supplemented in iron deficiencies in IBD?
- In inactive IBD- can give oral iron supplements - 100mg a day
- If active - give IV iron e.g. ferric carboxymaltose
Can NSAIDs be taken by patients with IBD?
Short-term is potentially safe but should be avoided as much as possible as can cause increase in disease activity and relapse
Can IBD patients be given opioids for pain relief?
Shouldn’t as they can cause constipation
- have poor IBD outcomes and risk of addiction
Can IBD patients have vaccinations?
It’s recommended you have the flu jab every year and the one-off pneumococcal vaccination.
But avoid having any live vaccines
Examples of aminosalicyclates used in IBD
Mesalazine
sulfasalazine
How does sulfasalazine work in IBD?
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
What monitoring is required for patients on aminosalicylates?
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
What may sulfasalazine do to urine?
May colour urine
May also make contact lenses go yellow
What are the different formulation mechanisms that change the release of Mesalazine in the GIT?
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
What tests need to be done prior to initiation of thiopurines (e.g. mercaptopurine, azathioprine)?
FBC
LFT
U&E
Vaccinate- flu and pneumococcal
up to date cervical screening
Check TPMT - Thiopurine methyl transferase- enzyme needed to breakdown mercaptopurine
What would you not do if a patient has a low TPMT level?
TPMT = Thiopurine methyl transferase- enzyme needed to breakdown mercaptopurine
If low = AVOID thiopurines e.g. mercaptopurine and azathioprine
What is the important drug interaction with Allopurinol?
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
What is the MOA of glucocorticoids in treating IBD?
- 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.
What is the MOA of Azathioprine?
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
How do aminosalicyclates work?
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
How does Ciclosporin work?
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
How does methotrexate work?
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
How do anti-TNF therapies work?
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
How do t-cell homing and retention therapies work?
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
What are the future and emerging therapies for use in IBD?
- 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?
