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GI Pharmacology

GI Pharmacology. Johann Graggaber SpR Clinical Pharmacology. Topics. Peptic ulcer disease/dyspepsia GORD Inflammatory bowel disease Irritable bowel syndrome Diarrhoea Constipation Pancreatitis. Dyspepsia / Peptic ulcer disease. Dyspepsia: upper abdo pain/discomfort

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GI Pharmacology

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  1. GI Pharmacology Johann Graggaber SpR Clinical Pharmacology

  2. Topics • Peptic ulcer disease/dyspepsia • GORD • Inflammatory bowel disease • Irritable bowel syndrome • Diarrhoea • Constipation • Pancreatitis

  3. Dyspepsia / Peptic ulcer disease Dyspepsia: upper abdo pain/discomfort (fullness, bloating, distension, nausea) Peptic ulcers defects in mucosa extending through muscularis mucosae Prevalence PUD 5-10% lifetime dyspepsia 25-40% Aetiology (most common) • H.pylori • NSAIDs

  4. Mucosa protective factors

  5. Parietal cell and acid regulation

  6. NSAIDs • Antiinflammatory • Analgesic • Antipyretic • Chemically heterogeneous • Reversible competitive inhibitors of COX activity (Aspirin irreversible) • Reduce prostaglandin synthesis (COX-1) • ↓ Mucus • ↓ bicarbonate • ↓ blood flow • ↓ proliferation of cells • ↑ gastric acid secretion • Reduce production of superoxide radicals, induce apoptosis, inhibit expression of adhesion molecules, decrease NO synthase and proinflammatory cytokines, modify lymphocyte activity and alter cellular membrane functions • Biliary excretion and reflux of metabolites into stomach

  7. Helicobacter pylori • Peptic ulcers • Gastric carcinoma/lymphoma • Mucosal atrophy Tests • Urea breath test (sens. and spec. ~95%) • Endoscopic (urease, histology) • Stool antigen (sens. and spec. ~ 95%) • (serology) • Omit PPI for 2 weeks prior to tests

  8. H. pylori

  9. Management of dyspepsia • Therapeutic trial of acid suppressing medication • H. pylori screening • Ifalarm features • GI bleeding • Unintentional weight loss • Progressive dysphagia • Odynophagia • Persistant vomiting • Iron deficiency anaemia • Mass/ suspicious barium meal • Do Endoscopy Gastric ulcer

  10. Treatment Lifestyle advice • Diet (alcohol, caffeine…) • Smoking Medication • Stop NSAIDs if possible • H-2 receptor antagonists • Proton pump inhibitors • H. pylori eradication • Antacids • Misoprostol (NSAIDs)

  11. H2 receptor antagonists • Cimetidine, Ranitidine, Famotidine, Nizatidine • Competitive and selective inhibition of histamine H-2 receptor • Suppress 24 hr gastric secretion by 70% • Less effective than PPI • Caution: renal failure, pregnancy, breast feeding • Interaction: Cimetidine binds to CYP 450 (retards oxidative drug metabolism) note interactions with warfarin, phenytoin, theophylline.. • Side effects • Well tolerated, less than 3% adverse effects • Diarrhoea, headache, drowsy, fatigue, constipation, CNS, LFT • Rarely pancreatitis, bradycardia, AV block, confusion (elderly, especially cimetidine) • Rarely blood dyscrasias

  12. Proton pump inhibitors • Omeprazole, Lansoprazole, Pantoprazole, Esomeprazole, Rabeprazole • Prodrugs activated in acidic secretory canaliculi • Inhibit gastric H+K+ ATPase irreversibly • Decrease acid secretion by up to 95% for up to 48 hours • Use: Ulcers, GORD, Zollinger-Ellison Syndrome, reflux oesophagitis • Side effects • Generally well tolerated • mc Gastrointestinal, headache, headache dizziness • Omeprazole – impotence, gynaecomastia • May increase risk of GI infections (reduced acidity) • Note: pH > 6 necessary for platelet aggregation Give high dose PPI in active GI bleed (eg Omeprazole 8mg/hr for 72 hrs)

  13. H. pylori eradication • Eradication increases ulcer healing • Reduces recurrence • MALT, Ca (can lead to resolution) Triple therapy For 7 (14) days twice daily eg • full dose PPI + • Amoxicillin + • Clarithromycin/Metronidazole Effective in 80-85%

  14. Other Antacids • Mg and Al hydroxides • May chelate other drugs (avoid concomitant administration of other drugs) • Side effects: diarrhoea (Mg), constipation (Al) • Milk alkali syndrome (alkalosis, renal insufficiency, hypercalcemia) Sucralfate • Forms sticky polymer in acidic environment • Inhibits hydrolysis of mucous proteins by pepsin • 1 g bd to 1g qds • SE: constipation, aluminium absorption (avoid in severe renal impairment due to risk of encephalopathy)

  15. Misoprostol • PGE1 analogue • Stimulates Gi pathway (↓cAMP and ↓gastric acid) • ↑ blood flow and ↑ mucus and bicarbonate secretion Use: prevention of NSAID induced injury Side effects: diarrhoea, pain, cramps (30%) Can cause exacerbation of IBD Contraindication: pregnancy, caution in women of childbearing age can induce labour!

  16. Nonvariceal Upper GI Bleed • Resuscitate (iv access, fluids, catheter, transfusion) • Bloods (cross match, FBC, U&E, clotting) • Drugs • Acid suppressing drugs (stabilize clot) • Somatostatin – reduces acid secretion and splanchnic blood flow • Antifibrinolytic drugs – tranexamic acid reduces need for surgery and mortality • +/- transfuse • Endoscopy: cause of bleeding, haemostasis (injection, clips, banding...), can usually wait until next day

  17. GORD Definition • Abnormal reflux of gastric contents into oesophagus • ± mucosal damage Prevalence • > 50% of population > once a year • 50% of patients have erosive oesophagitis Pathophysiology • Antireflux barrier (sphincter…) • Acid, pepsin, trypsin, bile acids, hiatus hernia

  18. Symptoms • Heartburn • Belching • Asthma, cough • Hoarseness, sore throat, globus Alarm features • GI bleeding • Unintentional weight loss • Progressive dysphagia • Odynophagia • Persistent vomiting • Iron deficiency anaemia • Mass/ suspicious barium meal

  19. Precipitants • Food (fatty food, alcohol, caffeine) • Smoking • Obesity • Medication • calcium antagonists, nitrates, theophyllines, NSAIDs, corticosteroids • Pregnancy Usually chronic relapsing course

  20. Diagnosis • Symptoms • Empirical therapy • Endoscopy • Failure of response to therapy • Alarm features • Barrett’s • 24-hour pH monitoring • pH < 4 • Limited sensitivity

  21. Complications • Oesophagitis • Strictures, ulcers • Barrett's

  22. Barrett's • Intestinal columnar metaplasia • Malignant potential • Needs surveillance

  23. Treatment Lifestyle advice • Dietary habits (fat, alcohol, caffeine, timing) • Smoking • Weight loss • Raising head • But little evidence for all those Medication • H-2 receptor antagonists • PPI • Antacids • Prokinetics

  24. Inflammatory Bowel Disease Ulcerative colitis • Diffuse mucosal inflammation limited to the colon Crohn's disease • patchy transmural inflammation • May affect any part of GI tract Features • UC bloody diarrhoea, colicky pain, urgency, tenesmus • CD abdominal pain, diarrhoea, weight loss intestinal obstruction systemic symptoms

  25. Drugs in IBD • Aminosalicylates • Corticosteroids • Thiopurines • Methotrexate • Ciclosporin • Infliximab

  26. Aminosalicylates • Sulfasalazine (5-aminosalicylic acid and sulfapyridine as carrier substance) • Mesalazine (5-ASA), eg Asacol, Pentasa • Balsalazide (prodrug of 5-ASA) • Olsalazine (5-ASA dimer cleaves in colon) • Oral, rectal preparation • Use • Maintaining remission • Active disease • May reduce risk of colorectal cancer • Adverse effects • 10-45% • Nausea, headache, epigastric pain, diarrhoea, hypersensitivity, pancreatitis, blood disorders, lung disorders, myo/pericarditis • Caution in renal impairment, pregnancy, breast feeding

  27. Corticosteroids • Antiinflammatory agents for moderate to severe relapses • eg 40mg Prednisolone • Inhibition of inflammatory pathways (↓IL transcription, suppression of arachidonic acid metabolism, lymphocyte apoptosis) • Side effects • Acne, moon face, oedema • Sleep, mode disturbance • Dyspepsia, glucose intolerance • Cataracts, osteoporosis, myopathy…

  28. Thiopurines Azathioprine, mercaptopurine • Inhibit ribonucleotide synthesis • Inducing T cell apoptosis by modulating cell signalling • Azathioprine metabolised to mercaptopurine and 6-thioguanine nucleotides Use • Active and chronic disease • Steroid sparing Side effects • Leucopaenia(myelotoxic) • Monitor for signs of infection, sore throat • Flu like symptoms after 2 to 3 weeks, liver, pancreas toxicity

  29. Methotrexate • Inhibits dihydrofolate reductase • Probably inhibition of cytokine and eicosanoid synthesis Use • Relapsing or active CD refractory or intolerant to AZA or Mercaptopurine • Monitor FBC, LFT Side effects • GI • Hepatotoxicity, pneumonitis

  30. Ciclosporin • Inhibitor of calcineurin, preventing clonal expansion of T cell subsets Use • Active and chronic disease • Steroid sparing • Bridging therapy Side effects • Tremor, paraesthesiae, malaise, headache, abnormal LFT • Gingival hyperplasia, hirsutism • Major: renal impairment, infections, neurotoxicity Monitor • Blood pressure, FBC, renal function

  31. Infliximab • Anti TNF-α monoclonal antibody • Potent anti inflammatory effects Use • Fistulizing CD • Severe active CD refractory/intolerant of steroids or immunosuppression • iv infusion Side effects • Infusion reactions • Sepsis • Reactivation of Tb, increased risk of Tb

  32. Principles of Managment of IBD • Assess severity • Mild and distal • topical steroids/aminosalicylates • Diffuse or not responding – • add oral steroids • Severe • admit, iv steroids, iv fluids, ?TPN etc • Ulcerative colitis: • Avoid antimotility drugs and antispasmodics as may precipitate paralytic ileus and megacolon

  33. Medical management of UC Active left sided/extensive • Aminosalicylate eg Mesalazine • Prednisolone 40mg (for prompt response or if mesalazine unsuccessful) – reduce dose gradually • Azathioprine for steroid dependant disease • Topical agents (rectal symptoms) • Ciclosporin for severe, steroid refractory colitis Active distal UC • Mild/Mod topical mesalazine (or steroid) + oral mesalazine • +/- oral steroids

  34. Severe UC • Admission for iv therapy • Close monitoring • Daily physical examination, regular vital signs, stool chart, CRP, AXR • FBC, ESR, CRP, U&E, albumin, LFT every 24-48 hours • Daily AXR if colonic dilatation (transverse >5.5cm) • Therapy • iv fluids and electrolytes if necessary • sc heparin (thromboembolism prophylaxis) • ? Nutritional support • iv steroids • Withdrawal of antidiarrhoeal agents (can precipitate dilatation) • Aminosalicylates • Topical therapy +/- surgical referral (colonic dilatation) Stool frequency (>8) and CRP (>45) on day 3 predict need for surgery Consider colectomy or iv ciclosporin

  35. Medical Management of CD • Assessment • Site, pattern (inflammation, stricturing, fistulating), prior disease activity • Confirm disease activity (CRP, ESR) • Active intestinal disease • Mild – aminosalicylate • Mod/severe – oral corticosteroids (reduce gradually over 8 weeks) • Severe – iv steroids • Elemental/polymeric diets • TPN (fistulating) • Azathioprine as steroid sparing agent • Consider surgery • Fistulating and perianal • Metronidazole +/- ciprofloxacin • Azathioprine • Infliximab • Other sites

  36. Maintenance of remission of CD • STOP SMOKING • Mesalazine of limited benefit • Azathioprine effective but toxicity • Methotrexate • Infliximab Steroid refractory disease • Definition • Active disease on >20 mg prednisolone > 2 weeks • Relapse when dose reduction • Azathioprine (monitor FBC) • MTX, Infliximab

  37. Constipation • Stool: 70-85% water (100ml/d) • Normal stool frequency ≥ 3/week Causes • Dietary (fibre), drugs, hormonal disturbances, neurogenic disorders • systemic illnesses, IBS • colonic motility • disorder of defecation or evacuation (outlet) Management • Diet, fluid, fibre rich diet • Avoidance of constipating drugs Only then consider medication (haemorrhoids, exacerbation of angina from straining…)

  38. Laxatives • Bulk-forming • Stimulant • Faecal softeners • Osmotic laxatives • Bowel cleansing solutions • Oral • Rectal-suppositories, enemas General Contraindications: intestinal perforation and obstruction

  39. Bulk-forming laxatives • Increase faecal mass which stimulates peristalsis • Bulk/softness/hydration dependant on fibre • Ensure adequate fluid intake (obstruction) • Effect can be delayed by a few days • Try dietary fibre first! • Wheat bran, oat bran, bran buiscuits • Pectins/hemicellulose (fruits, vegetables) • Ispaghula (Fybogel, Isogel) • Methylcellulose (Cevelac) • Sterculia (Normacol) • Contraindication: intestinal obstruction, colonic atony, faecal impaction • Side effects: flatulence, abdominal distension, GI obstruction, rarely hypersensitivity

  40. Stimulant Laxatives • Increase intestinal motility Diphenylmethane derivatives • Sodium picosulfate, hydrolyzed by bacteria to active form, effects vary • Bisacodyl (Dulco-lax), usually 5-10mg nocte Anthraquinone Laxatives • Require activation in colon (bacteria), onset of action delayed (6-12 hours) • Senna (Senokot), plant derivative • Danthron (Co-danthramer) possibly carcinogenic, only use in terminally ill Docusate Sodium stimulant and softening Glycerol suppositories (Parasympathomimetics such as bethanechol, neostimin rarely used) Side effects: cramps, diarrhoea, hypokalaemia

  41. Osmotic laxatives Osmotically mediated water retention • Nondigestible sugars and alcohols • synthetic disaccharide, resists intestinal disacharidase • draw water in osmotically, not absorbed • Lactulose • Use: elderly, opioids, hepatic encephalopathy (↓ ammonia production) • Magnesium salts • Phosphates (rectal, Fleet) • Sodium citrate (rectal, Micralax Micro-enema) • Polyethylene Glycol-Electrolyte Solutions - Macrogels • Sequester fluid in bowel, poorly absorbed • Movicol

  42. Faecal softeners - Emollients • Sodium docusate (stimulant and softening) • Arachis oil enemafor impacted faeces • Liquid Paraffin (oral solution) Side effects: anal irritation, interference with absorption of fat soluble vitamins, granulomatous reactions

  43. Bowel cleansing solutions • Before colonic surgery, colonoscopy and radiological examinations • eg Fleet, Klean-Prep, Picolax • Contraindications: obstruction, GI-ulceration, perforation, CCF, toxic colitis or megacolon, ileus • Side effects: nausea, bloating, cramps, vomiting

  44. Diarrhoea Definition • Excessive fluid weight (200g/day) Mechanism • Increased osmotic load • Excessive secretion (electrolytes and water) • Exudation of protein and fluid • Altered motility (rapid transit) • Often combined Management • Rehydration, maintain fluid and electrolyte balance • NaCl absorption linked with glucose uptake (rehydr. solutions) • Antimicrobial therapy. May mask clinical picture, delay clearance of organism, increase risk of systemic invasion.

  45. Antimotility drugs Opioids • μ (motility) and δ (secretion) receptors, absorption (both) • Loperamide – Imodium • 40-50x more potent than morphine • Poor CNS penetration • Increases transit time and sphincter tone • Antisecretory against cholera toxin and some E.coli toxin • T½ 11 hours, dose: 4 mg followed by 2mg doses (16mg/d max) • Overdose: paralytic ileus, CNS depression • Caution in IBD (toxic megacolon) • Codeine phosphate Other • Bismuth subsalicylate • Adsorbents such as Kaolin (not recommended), charcoal (insufficient data for adsorbents)

  46. Diarrhoea Clostridium difficile • Clinical suspicion, test for toxins (stool) • Metronidazole PO • Vancomycin PO

  47. Irritable bowel syndrome • Recurrent abdominal pain with disturbed bowel habits • 9-12% of population affected • ? Pathophysiology Treatment • Dietary modification • Psychological therapies • Fibre – binding water (diarrhoea and constipation) • Antispasmodics • Anticholinergic – Hyoscyamine, methscopolamine • Calcium channel antagonists and peripheral opioid receptor antagonists • Mebeverine: direct effect on smooth muscle cell • Tricyclic antidepressants • Analgesic and neuromodulatory properties • Loperamide, codeine

  48. Antispasmodics • Antimuscarinics • Reduce motility • Quaternary amines • eg hyoscine butylbromide (Buscopan) less lipid soluble and thus less well absorbed than atropine • CI: angle-closure-glaucoma, mysthenia, paralytic ileus, pyloric stenosis and prostatic enlargement • SE: constipation, transient bradycardia, reduced bronchial secretions, urinary urgency etc • Other • Direct relaxants of intestinal smooth muscle • No serious side effects but avoid in paralytic ileus • Alverine • Mebeverine • Peppermint oil (Colpermin)

  49. Pancreatitis Causes (mc) gallstones alcohol Diagnosis symptoms (abdominal pain, N&V) pancreas enzymes (amylase, lipase) USS +/- CT abdo severity scores (APACHE) Treatment rescuscitation (fluids + oxygen) symptomatic control (analgesia) prophylactic antibiotics if significant necrosis (30%) ?enteral nutritition chronic pancreatitis: pancreatin eg Creon

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