CPT2: GI 8 (ASA, steriods, immunosupressants)

Question 1

What does ASA stand for?

What is the main drug in this category?

Answer 1

Aminosaylacilates

Mesalazine

Question 2

What forms is mesalazine in?

Used for?

How do these work?

Where is it excreted?

Answer 2

Mesalazine (5-ASA)

• Used as first line treatment in ulcerative colitis. No proven value in Crohn’s.
• Topical anti-inflammatory effect on the bowel mucosa – systemic absorption has limited value
• Oral mesalazine must be in a gastro-resistant formulation – otherwise absorbed before the site of action.
• Rectal (suppository, foam, enema) can be used depending on site ‘Top and tail’
• ØRenal excretion (dehydration potential, nephrotoxic)
• Oral mesalazine preparations are formulated to release in different ways:
  
  • Asacol - pH dependent (think about effect of lactulose)
  • Pentasa - time dependent
  • Formulations not interchangeable
• Side effects: diarrhoea, nausea, headache, arthralgia.
• Blood disorders: Agranulocytosis, thrombocytopenia
  
  • ​•NB: advise patients to report bleeding, bruising, sore throat, fever or malaise. FBC count and drug stopped immediately if suspicion of blood dyscrasias.
• •Monitor renal function. 5-ASA can affect renal function. Caution with NSAIDs and diuretics.

Question 3

Describe the use of steriods

Side effects

Warnings

Answer 3

• Corticosteroids – Budesonide, Prednisolone, Methylprednisone
• Used to induce remission in both Crohn’s and UC. Not used for maintenance.
• ØPotent anti-inflammatory which inhibits several anti-inflammatory pathways e.g. interleukin transcription, downregulation of chemotaxis, reduction in pro-inflammatory mediators (histamine, prostaglandins)
• ØBudesonide less effective, but less side effects. Maybe give to patient on first relapse
• ØAvailable oral, rectal and IV
• Short term side effects: Moon facies, oedema, sleep and mood disturbances, dyspepsia, weight gain and elevated blood glucose, raised blood pressure.
• Long term side effects: Cataracts, osteoporosis, myopathy, susceptibility to infections, risk of T2DM (Cushing’s like symptoms)
• Abrupt withdrawal of long term treatment: acute adrenal insufficiency, disease flare
• Supply steroid card

Question 4

What is an example of an immunosupressant and how does it work.

Side effects

Risks

Answer 4

Mercaptopurine, Azathioprine (prodrug of 6-MP)

• Incorporated into replicating DNA and RNA - blocking synthesis of purines and blocking growth of fast growing cells, including immune cells à immunosuppression.
• Takes 2-6 months for max effect
• Maintenance of Crohn’s
• Step up therapy in UC
• Can’t be used alone to induce remission
• Side effects: flu like symptoms, nausea, hepatotoxicity, pancreatitis, bone marrow suppression
• Frequent FBC and LFTs required
• increased risk of skin cancers
• Thiopurine Methyltransferase (TPMT) activity level must be assessed prior to starting treatment.#
• Thiopurine S-methyltransferase (TPMT) metabolises and detoxifies 6-MP. TPMT deficiency results in significant bone marrow toxicity.
• Allopurinol is a xanthine oxidase inhibitor used in gout – dose may need to be reduced to prevent toxicity of azathioprine
• Red flag symptoms: sore throat, cough, bruising, fever (bone marrow suppression), abdo pain, dark urine, jaundice (liver/pancreas)

Question 5

Use of biologics

Answer 5

TNFα inhibitor – Infliximab, Adalimumab, Golimumab (IV/subcutaneous)

ØBind to tumour necrosis factor alpha (TNFa) and prevent further immune activation.

ØAdalimumab and golimumab available as subcutaneous injection

Integrin Blocker – Vedolizumab

ØPrevents entry of certain white cells into the bowel mucosa

IL-12 and IL-23 Blocker – Ustekinemab

ØPrevents actions of cytokines IL-12 and IL-23 on immune cells

ØAvailable as subcutaneous injection

ØRequires 1st dose (loading) in hospital

Ø

Adverse effects: risk of hypersensitivity, risk of infection/reactivation, flu-like symptoms, nausea, diarrhoea, skin reactions

Question 6

Methotrexate

Used when

Mechanism

Side effects

Monitoring

Drug interactions?

Answer 6

Methotrexate

Inhibits dihydrofolate reductase (folate antagonist), preventing DNA/RNA/protein synthesis and growth of fast growing cells. Accumulation of some purine precursors also has an anti-inflammatory effect.

ØInduces remission and prevents relapse in Crohn’s where Azathioprine is ineffective/not tolerated.

ØNo proven benefit in UC.

ØAvailable as oral and subcutaneous injection

ØGI side effects limited with folic acid 5mg

ØONCE weekly. NHS Grampian only supply 2.5mg tablets (instead of 10mg) to prevent errors.

Side effects: nausea, fatigue, vomiting, diarrhoea, stomatitis

hepatotoxicity, pneumonitis, bone marrow suppression

• Teratogenic - contraception
• Renal excretion – avoid nephrotoxins if possible
• Avoid other medicines associated with bone marrow suppression (Co-trimoxazole, also antifolate)
• Frequent FBC and LFTs required