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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
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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
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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)
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Acute attack 800mg TDS; remission 800mg BD (400-800mg)
— Foam enema (1g/metered applications)
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Acute attack L-sided disease 1-2g PR OD; remission 1g OD
— Suppositories (250mg)
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0.5-1g daily divided doses, last dose bedtime
 Pentasa
— Pentasa slow release tablets (500mg)
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Acute attack 2g BD; Maintenance 1g BD
— Prolonged release granules (1g sachet)
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Acute attack 2g BD; Maintenance 1g BD
— Suppositories (1g)
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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
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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
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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
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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
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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)
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Side Effects:
 Acute hypersensitivity reactions: fever, pruritis, urticaria, chest pain,
SOB, hypo-/hypertension
— 30 minute obs & access to resus equipment during infusions
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Mild reaction: slow down/temporarily stop infusion
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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
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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
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