IBD - Drugs

What are the 5 main classes of IBD drugs?

Corticosteroids, Azathioprine, 5-aminosalicylates (5-ASA), Ciclosporin, Methotrexate.

How do corticosteroids work? (Step by step)

Step 1: Steroid enters the cell and binds to glucocorticoid receptor (GR) in the cytoplasm. Step 2: GR is held by heat-shock proteins (hsp90, hsp70). Step 3: Steroid binding activates GR, forming a homodimer. Step 4: The complex moves into the nucleus. Step 5: It blocks pro-inflammatory transcription factors NF-κB and AP-1. Step 6: This prevents production of IL-6 and leukotrienes. Step 7: It also increases IκBα, which binds to NF-κB and traps it in the cytoplasm.

What is the role of IκBα in corticosteroid action?

IκBα binds to NF-κB and keeps it in the cytoplasm, stopping it from entering the nucleus and activating inflammatory genes.

What is azathioprine?

An immunosuppressive antimetabolite and a prodrug of 6-mercaptopurine (6-MP).

How is azathioprine activated? (Step by step)

Step 1: Azathioprine is converted to 6-mercaptopurine (6-MP). Step 2: 6-MP is activated via the enzyme HGPRT. Step 3: It is converted to thioguanine nucleotides (6-TGN). Step 4: 6-TGN is incorporated into DNA. Step 5: This inhibits DNA, RNA, and protein synthesis. Step 6: T cell proliferation stops.

What are the two inactivation pathways for azathioprine?

Pathway 1: TPMT (thiopurine methyltransferase) – methylates and inactivates metabolites. Pathway 2: XO (xanthine oxidase) – oxidises to thiouric acid.

What is the Rac1 mechanism of azathioprine? (Step by step)

Step 1: Azathioprine is metabolised to 6-Thio-GTP. Step 2: 6-Thio-GTP binds to Rac1 instead of normal GTP. Step 3: This blocks Rac1 activation. Step 4: Without Rac1, MEK, NF-κB, and bcl-xL cannot be activated. Step 5: bcl-xL is an anti-apoptotic protein. Step 6: Without bcl-xL, the cell undergoes mitochondrial apoptosis. Step 7: Azathioprine converts a survival signal into a death signal.

What does 6-Thio-GTP do?

6-Thio-GTP binds to Rac1 instead of GTP, blocking Rac1 activation and converting a co-stimulatory signal into an apoptotic signal.

What is the active moiety of aminosalicylates?

5-aminosalicylic acid (5-ASA).

Name the 5-ASA prodrugs.

Sulfasalazine, olsalazine, and balsalazide. (Mesalazine is a formulation, not a prodrug).

How does sulfasalazine deliver 5-ASA to the colon? (Step by step)

Step 1: Sulfasalazine is taken orally. Step 2: It reaches the colon unchanged. Step 3: Bacterial azoreductases cleave the azo bond. Step 4: This releases 5-ASA (active) and sulfapyridine. Step 5: Sulfapyridine is absorbed and causes side effects (nausea, headaches).

How does olsalazine deliver 5-ASA to the colon? (Step by step)

Step 1: Olsalazine is two 5-ASA molecules linked by an azo bond. Step 2: It reaches the colon. Step 3: Bacterial azoreductases cleave the azo bond. Step 4: This releases TWO molecules of active 5-ASA.

How does balsalazide deliver 5-ASA to the colon? (Step by step)

Step 1: Balsalazide is a prodrug. Step 2: It reaches the colon. Step 3: Bacterial azoreductases cleave the azo bond. Step 4: This releases 5-ASA (active) and an inert carrier. Step 5: The inert carrier is poorly absorbed, so fewer side effects.

What are the mechanisms of action of 5-ASA? (List 5)

Mechanism 1: Scavenges free radicals (reactive oxygen metabolites, ROM). Mechanism 2: Inhibits COX (prostaglandin synthesis). Mechanism 3: Decreases neutrophil chemotaxis. Mechanism 4: Inhibits NF-κB signalling. Mechanism 5: Inhibits TNF-mediated effects on epithelial proliferation.

How does 5-ASA affect reactive oxygen metabolites (ROM)?

Step 1: Inflammation causes neutrophils to produce superoxide radicals (ROM). Step 2: ROM cause oxidative DNA damage. Step 3: 5-ASA scavenges these free radicals. Step 4: This inhibits ROM generation and reduces oxidative DNA damage.

What is ciclosporin and where does it come from?

A lipophilic cyclic peptide of 11 amino acids, first isolated from fungi.

What is the mechanism of action of ciclosporin? (Step by step)

Step 1: Antigen binds to T cell receptor → increases intracellular calcium. Step 2: Calcineurin (a phosphatase) is activated. Step 3: Ciclosporin binds to cyclophilin. Step 4: The ciclosporin-cyclophilin complex inhibits calcineurin. Step 5: Without calcineurin, NF-AT cannot be dephosphorylated. Step 6: NF-AT cannot enter the nucleus. Step 7: IL-2 and other cytokine genes (TNF-α, IL-3, IL-4, IFN-γ) are not transcribed. Step 8: T cell proliferation is reduced.

What is calcineurin?

A calcium and calmodulin-dependent phosphatase that activates NF-AT. Ciclosporin inhibits calcineurin.

Which IBD is ciclosporin used for?

Ulcerative colitis (UC) – NOT Crohn's disease. It can induce remission in UC.

What is methotrexate (MTX)?

An antimetabolite of folic acid that inhibits dihydrofolate reductase (DHFR).

What is the mechanism of action of methotrexate? (Step by step)

Step 1: MTX enters the cell. Step 2: It inhibits dihydrofolate reductase (DHFR). Step 3: DHFR normally converts FH₂ to FH₄ (tetrahydrofolate). Step 4: Without FH₄, the cell cannot make thymidylate (dTMP) or purines. Step 5: Without thymidine and purines, DNA synthesis stops. Step 6: Rapidly dividing T cells cannot proliferate.

What other effects does methotrexate have?

Effect 1: Induces apoptosis by increasing intracellular reactive oxygen species (ROS). Effect 2: Suppresses proinflammatory cytokines (IL-6, IL-13, TNF-α, IFN-γ). Effect 3: Blocks adhesion molecules (E-selectin, ICAM-1, VCAM-1).

What is the enzyme TPMT and why is it important?

Thiopurine methyltransferase inactivates azathioprine. Patients with low TPMT activity have higher risk of toxicity (bone marrow suppression).

What is the enzyme HGPRT and its role in azathioprine activation?

Hypoxanthine-guanine phosphoribosyltransferase – converts 6-MP to active thioguanine nucleotides (6-TGN).

What is the difference between a prodrug and a formulation?

Prodrug = inactive until metabolised (e.g., azo bond cleavage by bacteria). Formulation = active drug but protected for targeted delivery (e.g., pH-dependent coating).

Which 5-ASA drug releases two molecules of active drug?

Olsalazine – two 5-ASA molecules linked by an azo bond.

Which 5-ASA drug causes the most side effects and why?

Sulfasalazine – releases sulfapyridine which causes nausea, vomiting, headaches, and dyspepsia.

What is the glucocorticoid receptor?

An intracellular receptor that binds corticosteroids. It is held in the cytoplasm by heat-shock proteins (hsp90, hsp70). Upon steroid binding, it moves to the nucleus.

What transcription factors do corticosteroids block?

NF-κB and AP-1 (activator protein 1).

What is the advantage of using ciclosporin in UC?

It can induce remission in severe UC and has steroid-sparing properties.

Why is methotrexate effective in IBD?

It stops T cell proliferation by blocking DNA synthesis, induces apoptosis via ROS, and reduces pro-inflammatory cytokines.

Complete the sentence: "Corticosteroids block the transcription factors ________ and ________."

NF-κB / AP-1

Complete the sentence: "Azathioprine is a prodrug of ________."

6-mercaptopurine (6-MP)

Complete the sentence: "6-Thio-GTP binds to ________ instead of GTP."

Rac1

Complete the sentence: "5-ASA scavenges ________ ________ metabolites (ROM)."

reactive oxygen

Complete the sentence: "Ciclosporin binds to ________ and inhibits ________."

cyclophilin / calcineurin

Complete the sentence: "Methotrexate inhibits the enzyme ________."

dihydrofolate reductase (DHFR)