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IBD Pharmacology 5-ASA → CCS → AZA (6MP) → (MTX) → Infliximab Aminosalicylates e.g. Sulphasalazine, mesalazine Known as 5-ASA (5-aminosalicylic acid) compounds Anti-inflammatory Indication: Mainstay therapy in CD & UC Acute disease (remission) & maintenance 1st line Rx for mild/moderate disease Sulphasalazine MOA: 5-ASA attached to sulphapyridine with a diazo bond Bacteria hydrolyse the diazo bond Side Effects: Nausea, headache (dose-related) Rash, male infertility (reversible) 15% pts don’t tolerate Side effects of 5-ASAs N&D, abdominal pain Agranulocytosis Headache Hepatitis Interstitial nephritis ↑Asthma in salicylate-sensitive Interactions: ↑Risk leucopaenia when 5-ASAs given with immunosuppressant e.g. AZA or 6-mercaptopurine Drugs that lower stool pH e.g. lactulose, may prevent mesalazine release Pharmacokinetics: Partly absorbed, metabolised by liver Majority is acetylated (to acetyl-mesalazine) by intestinal mucosa during passage through GIT Both mesalazine & acetyl-mesalazine are excreted in urine & faeces Mesalazine Indication: When sulphasalazine poorly tolerated No sulphonamide component As good as sulphasalazine & better tolerated MOA: Exact mechanism unknown Thought to work by inhibiting both COX & 5-lipo-oxygenase pathways of arachidonic acid metabolism → ↓inflammatory PG production Cautions: Renal impairment — Risk renal toxicity (esp in elderly); initial U&E then check regularly P&B Blood disorders can occur — Advise pts to report unexplained bleeding, bruising, purpura, sore throat, fever or malaise during Rx Contraindications: Salicylate hypersensitivity Severe hepatic impairment Mesalazine - well absorbed in small intestine so need a delivery mechanism: 1. Coated with Eudragit-S → pH-dependent release — E.g. Asacol – acts from terminal ileum onwards OR 2. Microparticles coated with ethylcellulose — E.g. Pentasa – acts from duodenum onwards Formulations Asacol — Asacol MR tablets (400-800mg) Acute attack 800mg TDS; remission 800mg BD (400-800mg) — Foam enema (1g/metered applications) Acute attack L-sided disease 1-2g PR OD; remission 1g OD — Suppositories (250mg) 0.5-1g daily divided doses, last dose bedtime Pentasa — Pentasa slow release tablets (500mg) Acute attack 2g BD; Maintenance 1g BD — Prolonged release granules (1g sachet) Acute attack 2g BD; Maintenance 1g BD — Suppositories (1g) Proctitis = 1 suppository OD 2-4/52; Maintenance = 1 OD Olsalazine MOA: 2 moeities of 5-ASA joined by diazo bond, split by bacteria → 5-ASA components → poorly absorbed in L-sided disease Indication: Active disease 1-3g/day; maintenance 0.5mg BD Side Effects: Diarrhoea (↓by titrating dose & taking with food) Immunosuppressants Azathioprine - 2mg/kg/day → can ↑ to 3mg/kg/day if WCC ok MOA: Cytotoxic, anti-proliferative immunosuppressant Metabolised to 6-Mercaptopurine (6MP); by enzyme TPMT Inhibits purine production → ↓ leucocytes → lymphopaenia Takes 3 months for clinical effect Indication: UC & CD Steroid-sparing agent 1st line immunosuppressant Interactions: Allopurinol ↑ effect & toxicity → ↓ dose ASAs ↑ risk of leucopaenia ↑ Risk toxicity with rifampicin, trimethoprim & co-trimoxazole Duration of Rx: Uncertain — CD – prob ok to stop after 4 years — UC – v.likely to relapse (esp if ↑CRP, ↓Hb, non-smoker) Wean slowly if need to stop 6-Mercaptopurine MOA: Anti-metabolite, cytotoxic immunosuppressant Works same way as AZA with same SEs → requires same monitoring Indication: If AZA ineffective Maintenance therapy Contraindications: If pancreatitis with AZA (will recur) Others the same as for AZA Cautions: ↓Dose in hepatic/renal impairment & elderly Contraindications: Hypersensitivity to AZA or 6MP P&B TPMT deficiency (enzyme which converts AZA → 6MP) — ↑Risk of myelotoxicity Side Effects: Myelosuppression (reversible) — Monitor for toxicity throughout Rx (can occur at any time) — Check FBC weekly for 1st 4/52; then every 3/12 — Pts should report: sore throats, infections, unexplained bleeding/bruising N&V&D Hepatitis Pancreatitis – withdraw AZA Pneumonitis Myalgia, arthralgia Fever, rigors Methotrexate – 25mg/week IM for 12/52 → if effective → 7.5-15mg/week PO MOA: Anti-metabolite folic acid inhibitor — Prevents DNA synthesis & cell division → immune suppression → disease improvement Immunosuppressant & anti-inflammatory 2-4/52 to take effect Indication: CD only e.g. failure to respond to steroids/intolerant of AZA 2nd line immunosuppressant Cautions: Liver & renal disease Obesity DM Contraindications P&B Alcohol Infections Side Effects: N&D, stomatitis – 10% Leucopaenia Pulmonary fibrosis Hepatitis, liver fibrosis (related to cumulative dose) Additional points: Monitor FBC, U&Es & LFTs at baseline then every 2-4/52 until treatment stabilised Take with folic acid 5mg 3x/week Interactions: NSAIDs Abx Antiepileptics e.g. phenytoin Pharmacokinetics: Metabolised in liver Infliximab MOA: Mab against TNFα (mouse-human chimeric Mab) Binds to soluble TNFα & TNFα on surface of T cells — TNFα is a pro-inflammatory cytokine — Binds to TNFα receptors on target cells → local & systemic effects — Causes local inflammation in GIT → diarrhoea & malabsorption Indication: NICE guidelines: — Severe active Crohn’s disease AND — Refractory to immunomodulatory drugs/cannot tolerate SEs/experienced toxicity AND — Surgery inappropriate Very good for fistulising disease Can also be prescribed for acute UC unresponsive to IV hydrocortisone Cautions: Previous TB HF, renal/hepatic impairment Mouse allergy Contraindications: Sepsis LFTs 3x normal Hypersensitivity to infliximab Active TB P&B (avoid for 6/12 after) Side Effects: Acute hypersensitivity reactions: fever, pruritis, urticaria, chest pain, SOB, hypo-/hypertension — 30 minute obs & access to resus equipment during infusions Mild reaction: slow down/temporarily stop infusion Severe reaction: stop & give IV hydrocortisone Delayed hypersensitivity reaction up to 2/52 post-infusion — More likely if >12/52 between infusions Development of Abs to Mab → ↓ response to infliximab ↑Risk of lymphoma/malignancy - esp if on other immunosuppressants ↑Infections – VZV, candida TB reactivation Interactions: Tacrolimus Live vaccines Additional points: Consultant-prescribed Infusions at week 0, 2 & 6 If respond, use as maintenance therapy every 8/52 EBM Endoscopic & clinical remission in unresponsive CD ↑Remission & response rates in fistulising CD