IBD

Question 1

Treatment Overview IBD

Answer 1

• aminosalicylates (activation of PPARγ): Mesalazine, Sulfasalazine
• immunosuppressants (decreased lymphocyte proliferation): Cyclosporin + Tacrolimus (Calcineurin-Inh.), Azathioprine
• Methotrexate
• TNFα blockers: Adalimumab, Infliximab
• glucocorticoids (decreased cytokine expression): Prednisolone, Budesonide
• Integrin inhibitor: Vedolizumab

Question 2

Aminosalicylates

Answer 2

e.g. Mesalazine, Sulfasalazine (IBD)

MOA: anti-inflammatory effect!

1. COX inhibition
2. activation of PPARγ → inhibition pro-inflammatory cytokines (LTB4, IL-1, IL-6, TNF-a, NF-kB)
3. activation of Hsp72 (→ fewer ROS)
4. inhibition of macrophage functions

Question 3

Mesalazine

Answer 3

• Aminosalicylate (IBD)
  = 5-aminosalicylic acid, 5-ASA)
• COX-I. activation of PPARγ + Hsp72, inhibition of macrophage functions
• active from jejunum to rectum
• bioavailability max. 20 % → local effect
• taken by mouth or rectally to target disease lesions

Question 4

Sulfasalazine

Answer 4

• Aminosalicylate (IBD)
• prodrug:
  colon microbiota metabolizes it to sulfapyridine + mesalazine
  → Mesalazine: local effect (only in colon!!!)
  → sulfapyridine is absorbed: systemic immunosuppression

Question 5

Cyclosporine

Answer 5

Calcineurin Inhibitor (Immunosuppressant) (IBD)
forms complex with cyclophilin that blocks phosphatase activity of calcineurin
→ prevents desposphorylation of NF-AT
→ reduced effector T-cell function (= T helper cell)

Question 6

Tacrolimus

Answer 6

Calcineurin Inhibitor (Immunosuppressant) (IBD)
forms complex with immunophilin PKBP12 that inhibits calcineurin
→ prevents desposphorylation of NF-AT
→ reduced effector T-cell function (=T helper cells)

Question 7

Calcineurin Inhibitor

Answer 7

Immunosuppressant (IBD)

• e.g. Cyclosporine, Tacrolimus
• werden auch bei Organtransplants eingesetzt
• inaktivieren die Phosphatase Calcineurin

Physiology:
antigenpräsentierende Zelle interagiert mit T-Zell-Rezeptor: Anstieg des Ca2+-Spiegels in der T-Zelle
→ Calcineurins wird durch Ca2+ aktiviert
→ Calcineurin dephosphoryliert + aktiviert den Transkriptionsfaktor NF-AT
→ NF-AT stimuliert Transkription von Zytokinen (Interleukin-2)
→ IL-2 aktiviert T-Helferzellen und induziert die Produktion weiterer Zytokine

Question 8

Azathioprine

Answer 8

Immunosuppressant (IBD)
- prodrug of 6-mercaptopurine
- inhibition of purine synthesis
→ less DNA/RNA is produced for lymphocyte proliferation
→ antiproliferative & immunosuppressive effect

Question 9

Vedolizumab

Answer 9

integrin antagonist (IBD)

• MOA:
  monoclonal antibody against α4β7-integrin of intestinal T-helper-cells (CD4+)
  → crucial for lympocyte invasion into gut endothelium
  → inhibition of lymphocyte adhesion to MAdCAM-1 of gut endothelial cells
  → gut-selective (!) anti-inflammatory activity = much less ADR than TNF-alpha blockers!

Question 10

Methotrexate

Answer 10

Ind: IBD, aber auch cancer und all sorts of autimmune diseases

MOA: competitive inhibition of dihydrofolate reductase (DHFR) = “antifolate“
- MTX-affinity for DHFR is 1,000x that of folate
- DHFR catalyses conversion DHF into THF
→ folate is essential for purine & pyrimidine base synthesis → inhibition of synthesis of DNA, RNA, thymidylates, proteins → cytostatic effect (that also affects lymphocytes)
- teratogenic effect of late deficiency (neural tube defects)

Question 11

TNFα blockers

Answer 11

Ind: IBD + other autoimmune diseases
- Infliximab, Adalimumab
MOA:
IgG monoclonal antibodies against soluble & transmembrane TNFα
→ prevent binding of TNFα with its receptors
→ neutralise biological activity of TNFα

ADR: many: 
- severe infections, reactivation of Hep B & tuberculosis
- drug-induced lupus
- demyelinating CNS disorders
- leukopenia, neutropenia, pancytopenia (some fatal) 
- arrhythmias, cardiotoxicity
- depression, diabetes, asthma
→ 3rd line of therapy only!

Question 12

Glucocorticoids for IBD

Answer 12

MOA: agonist at intracellular GC receptors
→ translocation to nucleus + binding to GRE on DNA
→ modulation of gene expression:
- decreased interleukin transcription
- stabilisation of NF-κB complex
- decreased COX-2 activity
- apoptosis of lymphocytes in the lamia propria
→ anti-inflammtory & immunosuppressive effects

• systemic GCs: prednisone, prednisolone
• topical Gas: budesonide:
  bioavailability < 5 % because presystemic elimination by intestinal CYP3A4 → only few systemic ADR

IND bei IBD: acute treatment of active disease
(not used during IBD remission)

CI: acute infection
ADR: < 7 days: almost no ADRs
with prolonged therapy: many ADRs (steroid acne, infections, peptic ulcers, diabetes = Morbus Cushing)