WK7- treatment of Crohns disease and IBD

What is the active moiety of all aminosalicylates?

5-aminosalicylic acid (5-ASA).

What is the problem with sulfasalazine?

Up to 1/3 of patients are intolerant. Side effects (nausea, vomiting, dyspepsia, malaise, headaches) are caused by the sulfapyridine moiety.

What are the proposed mechanisms of action of 5-ASA?

Mechanism 1: Scavenges free radicals. Mechanism 2: Inhibits prostaglandin and leukotriene production. Mechanism 3: Decreases neutrophil chemotaxis and superoxide generation.

Why is oral administration of plain 5-ASA tablets ineffective?

Step 1: Transit time through small bowel is slow. Step 2: Most of the drug is absorbed before reaching the colon. Step 3: 5-ASA is also inactivated by acetylation in gut epithelium and liver.

What is mesalazine?

A formulation of 5-ASA in a pH-dependent modified release tablet that delivers 5-ASA to the distal small bowel and colon.

How does balsalazide deliver 5-ASA to the colon?

Step 1: Balsalazide is a prodrug with an azo bond. Step 2: Azo bond is cleaved by bacterial azoreductases in the distal bowel. Step 3: Releases 5-ASA (active) and an inert carrier (4-aminobenzoyl-β-alanine). Step 4: The inert carrier is poorly absorbed (fewer side effects).

How does olsalazine deliver 5-ASA to the colon?

Step 1: Olsalazine is two 5-ASA molecules linked by an azo bond. Step 2: Azo bond is cleaved by bacteria in the distal small bowel and colon. Step 3: Releases TWO molecules of 5-ASA.

How does sulfasalazine deliver 5-ASA to the colon?

Step 1: Sulfasalazine has an azo bond. Step 2: Cleaved by bacterial azoreductases in the colon. Step 3: Releases 5-ASA (active) and sulfapyridine (causes side effects).

What are the three structural modifications that improved corticosteroid activity?

Modification 1: Δ¹,² double bond. Modification 2: 9α-fluoro substituent. Modification 3: 16α-hydroxy or 16α/16β-methyl group.

What does the Δ¹,² double bond do to corticosteroids?

Step 1: Changes A-ring geometry from half-chair to flattened boat. Step 2: Increases glucocorticoid (GC) receptor affinity. Step 3: Gives prednisolone (4 times more active than cortisol with fewer side effects).

What does the 9α-fluoro substituent do to corticosteroids?

Step 1: Increases glucocorticoid (GC) activity. Step 2: Fludrocortisone is 11 times more potent than cortisone. Step 3: BUT – it also increases mineralocorticoid (MC) activity by 300-800 fold (bad – causes fluid retention).

What does the 16α-hydroxy group do to corticosteroids?

Reduces mineralocorticoid (MC) activity without affecting glucocorticoid (GC) activity. Example: triamcinolone.

What does the 16α/16β-methyl group do to corticosteroids?

Step 1: Increases glucocorticoid (GC) activity by increasing lipophilicity and receptor affinity. Step 2: Also reduces mineralocorticoid (MC) activity. Step 3: Examples: dexamethasone and betamethasone.

Which corticosteroid is preferred for IBD and why?

Prednisolone – it is 4 times more active than cortisol due to the Δ¹,² double bond.

Which corticosteroid is favoured for mild IBD and why?

Budesonide – it acts principally in the gut (high first-pass metabolism), so fewer systemic side effects.

What are thiopurines?

Antimetabolites that inhibit ribonucleotide synthesis. Used when patients are unresponsive to steroids and aminosalicylates.

What is the relationship between azathioprine and 6-mercaptopurine?

Azathioprine is a prodrug of 6-mercaptopurine (6-MCP).

What is the advantage of azathioprine over 6-mercaptopurine?

Step 1: 6-MCP is eliminated too quickly. Step 2: Azathioprine is slowly converted to 6-MCP by reaction with glutathione. Step 3: This allows for more sustained activity.

What is the role of the NO₂ group in azathioprine?

The NO₂ group is electron-withdrawing. The greater the electron-withdrawing ability of the heterocyclic group, the faster the breakdown to 6-MCP.

What are biologics?

Monoclonal antibody therapies used for moderate to severe Crohn's disease when azathioprine is not working.

What is the target of infliximab and adalimumab?

TNF-α – they are anti-TNF antibodies.

What is vedolizumab and how does it work?

Vedolizumab is a gut-selective integrin blocker. It binds to α₄β₇ integrin on T cells, blocking their homing to the gut lining.

What are the three major classes of drugs for IBD from a med chem perspective?

Aminosalicylates, corticosteroids, and thiopurines.

Complete the sentence: "The active component of aminosalicylates is ________."

5-ASA (5-aminosalicylic acid)

Complete the sentence: "Sulfasalazine, olsalazine, and balsalazide are ________ of 5-ASA."

prodrugs

Complete the sentence: "Prednisolone is more active than cortisol due to its ________ double bond."

Δ¹,²

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

6-mercaptopurine (6-MCP)