Pharm 20 - Pharmacology of IBD Flashcards
What are the the 2 forms of IBD?
- Ulcerative colitis (UC)
- Crohns Disease (CD)
Roughly 10% have indeterminate colitis (unclear distinction)
Obesity is a RF for which form of IBD?
CD, not a RF for UC
Name 4 RFs for IBD
- Genetic predisposition (163 loci)
- Smoking
- Diet
- Gut microbiome
What is the pathogenesis of the disease
Improper interaction between mucosal immune system and gut flora
UC is mediated by which helper cell?
Th1
CD is mediated by which helper cell?
Th2
Which cytokines influence UC
IL-5 and IL-13
What is the main cytokine in CD
TNF-a
Which gut layers does UC affect
Mucosa and submucosa
Which gut layers does Crohns affect
All layers
What differences are there in pattern of inflammation of UC. vs CD
UC = continuous inflammation
CD = patchy inflammation
Where does UC start and spread?
Starts at rectum and spreads proximally
UC is curative why.
Surgery to remove affected piece of bowel and it won’t reoccur.
Is CD curative
No, as it may reoccur.
CD more likely to get abscesses, fissures and fistulae
IBD can have systemic effects?
Y
What are the supportive therapies for IBD
- Fluid/electrolyte replacement
2. Nutritional support
What are the symptomatic treatments for IBD
- Glucocorticoids (e.g. prednisolone)
- Aminosalicylates (e.g. mesalazine)
- Immunosuppressives (e.g. azathioprine)
What are the potentially curative therapies for IBD and how do they work
Manipulate gut microbiome
- Anti-TNF a (e.g. infliximab)
- Anti-a-4-integrin (e.g. natalizumab)
Aminosalicylates are more effective in treating which form of IBD
UC - first line for inducing and maintaining remission
Give 2 examples of aminosalicylates
Mesalazine (aka 5-aminosalicylic acid - 5-ASA)
Olsalazine - more complex as it consists of 2 5-ASA molecules)
What property do aminosalicylates have that makes them useful
Anti-inflammatory
How are aminosalicylates anti-inflammatory?
They inhibit:
- IL-1
- TNF-a
- Platelet activating Factor (PAF)
They also decrease antibody secretion and cell migration.
Mesalazine does not need to be metabolised - where is it absorbed
In the small bowel and colon
Olsalazine (5-ASA derivative) is only absorbed in the colon. Why
It is a more complicated drug and must be activated by colonic flora
Combined therapy of topic 5-ASA and oral what is ideal for inducing remission of UC?
Oral steroids. (though topical 5-ASA better than topical steroids alone)
Which are better for treating UC; aminosalicylates or glucocorticoids?
Aminosalicylates
Though glucocorticoids can be used topically/IV if severe
What are the drugs of choice for inducing remission in Crohns disease?
Glucocorticoids (side effects possible)
Name 2 properties of glucocorticoids (e.g. prednisone, fluticasone, budesonide)
- Anti-inflammatory
2. Immunosuppressive
What receptors do glucocorticoids act on?
Intracellular glucocorticoid receptors
3 strategies for minimising side effects of glucocorticoids
- Topical administration
- Low dose in combination with another drug
- Use topically administered drug w high hepatic first pass metabolism (e.g. Budesonide)
Budesonide has fewer side effects than which glucocorticoid
Prednisolone
Which immunosuppressive agent has shown success in both UC and CD
Azathioprine
Name 2 immunosuppressive agents aside from azathioprine
- Methotrexate
2. Cyclosporin - useful only in severe UC
Describe azathioprine and when it is used
- Immunosuppressive
- Used to maintain remission in CD- better than placebo and budoneside
- “Steroid-sparing”
- Has slow onset - 3/4 months required before seeing effects
How does azathioprine have its immunosuppressive effects
Azathioprine = prodrug activated in vivo by gut flora to 6-mercaptopurine - purine antagonist - interferes w/ DNA synthesis and cell replication
What does azathioprine impair
- Cell/antibody mediated immune responses
- Lymphocyte proliferation
- Mononuclear cell infiltration
- Antibody synthesis
What does azathioprine enhance
T cell apoptosis
Name 4 side effects of azathioprine
- Pancreatitis
- Bone marrow suppression
- Hepatotoxicity
- Increased risk of lymphoma and skin cancer
Which is the most ideal metabolism pathway for azathioprine?
XO pathway (xanthine oxidase pathway) - inert metabolites produced
This is also the main pathway
What cant you coadminister with azathioprine
Allopurinol - inhibitor of Xanthine oxidase, causing production of toxic metabolites
Allopurinol is used to treat gout
What is methotrexate an antagonist for?
Folate
What does methotrexate have a demonstrable effect for?
CD
What does methotrexate reduce synthesis of?
Thymidine / other purines
Not used as there are many side effects
3 ways in which the micro biome can be manipulated for UC/CD
- Nutrition based therapies - no evidence in CD but evidence in UC
- Faecal microbiota replacement therapies (FMT) - insufficient evidence
- Antibiotic treatment - Rifaximin - interferes with bacterial transcription by binding to RNA polymerase (good for moderate CD and potentially UC)
Which 2 anti-TNF-a antibodies are used for IBD (mainly CD)
- Infliximab (IV)
- Adalimumab (SC)
(these are potentially curative for CD)
Why are anti-TNF-a antibodies not as effective for UC
UC = th2 mediated
TNF-a is a th1 cytokine
Describe how anti-TNF-a antibodies work
- Reduce activation of TNF-a receptors in the gut, also binds to membrane associated TNF-a
- Downregulating TNF-a down regulates other cytokines (as TNF-a top of inflammatory cascade)
- Reduced infiltration and activation of leukocytes
- CYTOLYSIS of cells expressing TNF-a
- APOPTOSIS of activated T-cells
How often is infliximab given?
IV injection given every 8 weeks (benefits can last unto 30 weeks after 1 infusion but patients relapse after 8-12 weeks)
What are adverse side effects of anti-TNF-a antibodies
Knocking out key cytokine in inflammatory cascade
4-5x increase incidence of (/reactivating) TB and other infections (e.g. septicaemia)
Also can worsen heart failure, demyelinating disease, malignancy
Why might responders lose response with anti-TNF-a antibodies?
The body develops anti-drug antibodies and increases drug clearance
Name 3 potential targets for biological therapies
- Alpha-4-integrin (cell adhesion molecule)
- IL-13 - particularly UC
- Janus kinases 1,2,3 - block signalling by il-2,4,9,15,21 (useful in UC)
