2.3 IBD medication Flashcards
Pharmacology of IBD
Supportive therapies – acute
- Fluid/electrolyte replacement
- Blood transfusion/ oral iron (e.g. for severe bloody diarrhoea)
- Nutritional support
- Antibiotics (not clear whether any particular bacterial species are causative)
Nutrition-based therapies – for maintenance of remission
- Probiotics e.g. lactobacilli, ___________ (“friendly
bacteria”)
- Current evidence base is weak in adults who tend to be poorly compliant
- _______________
Treatment of symptoms – active disease and prevention of relapse
- Glucocorticoids e.g. Prednisolone
- Aminosalicylates e.g. Mesalazine
- Immunosuppressives e.g. Azathioprine
Potentially curative therapies – largely monoclonal antibodies against specific endogenous mediators
- Anti-TNF α e.g. infliximab
- Anti-α4-integrin e.g. _____________
bifidobacteria;
Omega 3 fatty acids;
natalizumab
Aminosalicylates – MESALAZINE or 5-aminosalicylic acid (5-OASA) is the active compound with anti inflammatory properties (____________ – 2 linked 5 ASA molecules)
Ulcerative colitis
- Useful in the treatment of active disease
- Useful for maintenance of remission
Crohn’s disease
- Ineffective in active disease
- May help maintain surgically induced remission
- Less clear-cut utility than for UC
Mesalazine
- site of absorption: _______________
Olsalazine – 2 linked 5-ASA
- Activated by Colonic flora – splits the 2 5-ASA monomers. Thus, olsalazine is a prodrug until it reaches the colon
- Site of absorption: __________
- Topical 5-ASA is superior to topical steroids in inducing UC remission –______________ better at inducing remission in UC than oral 5-ASA alone
OLSALAZINE;
Small bowel and colon;
Colon;
combined oral and topical 5 ASA
Immunosuppressive agents – a number of different drugs have been tried, but there is limited success
- Azathioprine – demonstrated a significant degree of success in ___________________________
- Methotrexate – demonstrable efficacy in some IBD patients
- Cyclosporin – useful in severe __________ only
- Azathioprine – immunosuppressive, mainly used to maintain remission in Crohn’s disease
- Can be used to induce remission in Crohn’s disease – requires prolonged treatment of ___________
- May enable reduction of glucocorticoid dose or postponement of colostomy
- Useful for maintaining remission some patients with ulcerative colitis
- Mechanism of immunosuppression – azathioprine is a pro-drug activated in vivo by gut flora to ________________ (it is possible to give directly)
o Interferes with ____________ and thus DNA synthesis and cell replication
o Impairs cell and antibody-mediated immune responses, lymphocyte proliferation, mononuclear cell infiltration and synthesis of antibodies
o Enhances ________________-
- Can cause Bone marrow suppression
- Metabolised by xanthine oxidase – co-administration of drugs which inhibit xanthine oxidase e.g. ____________ can cause build-up of 6-mercaptopurine leading to blood disorders
o Monitoring of metabolites can be used to predict safety and monitor efficacy - Methotrexate – acts as a ____________, reduces synthesis of thymidine and other purines
- Not widely used as there is significant unwanted effects – in over 40% recipients in some studies
both ulcerative colitis and Crohn’s disease;
ulcerative colitis;
> 17 weeks;
6-mercaptopurine;
purine biosynthesis;
T cell apoptosis;
allopurinol;
folate antagonist
Biologic therapies
- Anti-TNF α antibodies – INFLIXIMAB (IV), ADALIMUMAB (_____________)
o Other antibodies are effective too but have more side effects
- Anti-TNF α antibodies are used successfully in the treatment of CD – potentially curative rather than simply palliative
o Successful in some patients with refractory disease and fistulae
o Some evidence of effectiveness in UC - Mechanism of therapeutic effect of anti-TNF α antibodies in inflammatory bowel disease – can bind to both free and attached TNF α, increasing effectiveness
o Anti-TNF α reduces activation of TNF α receptors in the gut – as TNF α is important for initiation of cascades of immune reactions, production of other
cytokines, infiltration and activation of leukocytes is reduced
o Induces ___________ of cells expressing TNF α, promotes apoptosis of activated T cells - Pharmacokinetics – infliximab is given intravenously with a very long half-life (9.5 days), brenefits can last for 30 weeks after a single infusion
o Most patients relapse after 8 to 12 weeks – repeat infusion every 8 weeks - Adverse effects –
o 4 to 5x increase in incidence of _______________________
o Increased risk of septicaemia
o Worsening of heart failure
o Increased risk of demyelinating disease
o Increased risk of malignancy
subcutaneous;
cytolysis;
tuberculosis and other infections – also risk of reactivating dormant TB
Before using Infliximab in local setting, some tests are mandatory –
o ________________- – only performed if there is suspicion of active infection (e.g. fever, suspicion of ongoing sepsis)
o HBsAg and TB-spot – Infliximab increases the risk of TB and other infections and can cause a flare in Hep B carriers, pulmonary and extrapulmonary TB
§ Important to exclude both _______________ before starting anti- TNF a
§ TB-spot is useful for latent TB but a positive TB-spot is not indicative of active TB – in clinical practice, TB-spot and CXR are both ordered
- SONIC trial – infliximab, azathioprine, or combination therapy for Crohn’s disease (investigated 500 patients with Crohn’s for 30 weeks)
o Combined infliximab and azathioprine therapy reduces immunogenicity risk, but increases TB/malignancy risk further – early use better than last resort
o _______________________ might allow identification of patients most likely to benefit (2 to 4% risk of life threatening side effects, so targeted use would be good)
o Greater risk of infection or lymphoma - Other possible targets –
o Alpha-4-integrin – cell adhesion molecule
o ____________ – particularly in ulcerative colitis
o Janus kinases 1, 2, and 3 – block signalling by __________________ (lymphocyte activation and function) and ____________ (pro-inflammatory)
§ Particularly in ulcerative colitis
Blood cultures;
hepatitis B and tuberculosis;
C-reactive protein levels and endoscopy;
Interleukin 13;
interleukins 2, 4, 9, 15, 21;
IL-6 and INF-γ
