Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Gi drugs outline

6,186 views

Published on

  • Be the first to comment

Gi drugs outline

  1. 1. Pharmacology Drugs that Affect the Gastrointestinal System
  2. 2. Topics <ul><li>Peptic Ulcer Disease </li></ul><ul><li>Constipation </li></ul><ul><li>Diarrhea </li></ul><ul><li>Emesis </li></ul><ul><li>Digestion </li></ul>
  3. 3. Peptic Ulcer Disease Factors that Increase Acidity Factors that Protect Against Acidity
  4. 4. Peptic Ulcer Disease <ul><li>Factors Increasing </li></ul><ul><ul><li>H. pylori </li></ul></ul><ul><ul><li>NSAIDs </li></ul></ul><ul><ul><li>Acidic agents </li></ul></ul><ul><ul><li>Pepsin </li></ul></ul><ul><ul><li>Smoking </li></ul></ul><ul><li>Factors Decreasing </li></ul><ul><ul><li>Mucus production </li></ul></ul><ul><ul><li>Buffers </li></ul></ul><ul><ul><li>Blood flow </li></ul></ul><ul><ul><li>Prostaglandins </li></ul></ul>
  5. 5. Regulation of Gastric Acid Secretion
  6. 6. H 2 Receptor Antagonists <ul><li>Inhibits gastric acid secretion </li></ul><ul><li>No effect on H 1 receptors </li></ul><ul><li>cimetidine (Tagamet ® ) </li></ul><ul><li>ranitidine (Zantac ® ) </li></ul><ul><li>famotidine (Pepcid ® ) </li></ul><ul><li>nizatidine (Axid ® ) </li></ul>
  7. 7. H 2 Receptor Antagonists <ul><li>Indications: </li></ul><ul><ul><li>PUD </li></ul></ul><ul><ul><li>GERD </li></ul></ul><ul><ul><li>Prevention of aspiration pneumonia </li></ul></ul>
  8. 8. Proton Pump Inhibitors <ul><li>K + H + ATPase (Proton Pump) </li></ul><ul><li>Irreversible inhibition </li></ul><ul><ul><li>Must synthesize new enzyme </li></ul></ul><ul><ul><li>Long duration </li></ul></ul><ul><li>omeprazole (Prilosec ® ) </li></ul><ul><li>lansoprazole (Prevacid ® ) </li></ul>
  9. 9. Anticholinergics <ul><li>pirenzepine (Gastrozepine ® ) </li></ul><ul><li>Other anticholinergics have too many side effects and are not used </li></ul>
  10. 10. Prostaglandin Analog <ul><li>misoprostol (Cytotec ® ) </li></ul><ul><ul><li>Approved for treating PUD due to long term NSAID use </li></ul></ul>
  11. 11. Antacids <ul><li>Increase pH of gastric environment </li></ul><ul><li>Hydroxides </li></ul><ul><ul><li>Aluminum </li></ul></ul><ul><ul><li>Magnesium </li></ul></ul><ul><li>Carbonates </li></ul><ul><ul><li>Calcium </li></ul></ul>
  12. 12. Antacids <ul><li>Most OTC drugs are combinations </li></ul><ul><ul><li>DiGel ® </li></ul></ul><ul><ul><li>Amphojel ® </li></ul></ul><ul><ul><li>Maalox ® </li></ul></ul><ul><ul><li>Milk of Magnesia ® </li></ul></ul><ul><ul><li>Mylanta ® </li></ul></ul>
  13. 13. Antibiotics <ul><li>Aimed at eliminating H. pylori </li></ul><ul><li>bismuth (Pepto-Bismol ® ) </li></ul><ul><li>metronidazole (Flagyl ® ) </li></ul><ul><li>amoxicillin (Amoxil ® ) </li></ul><ul><li>tetracycline (Achromycin V ® ) </li></ul>
  14. 14. Stool Formation <ul><li>Water absorbed in colon (~90%) </li></ul><ul><ul><li>Excessive absorption </li></ul></ul><ul><ul><ul><li>Constipation: hard, dehydrated stool </li></ul></ul></ul><ul><ul><ul><li>Increases strain on defecation </li></ul></ul></ul><ul><ul><ul><li>Harmful for subset of patients </li></ul></ul></ul><ul><ul><ul><ul><li>Recent episiotomy, colostomy, hemorrhoids, cardiovascular disease </li></ul></ul></ul></ul><ul><ul><li>Inadequate absorption </li></ul></ul><ul><ul><ul><li>Diarrhea: soft, non-formed, liquid stool </li></ul></ul></ul>
  15. 15. Terms <ul><li>Laxative </li></ul>Production of soft, formed stool over 1 or more days Cathartic Rapid, intense fluid evacuation of bowel.
  16. 16. Laxatives <ul><li>Bulk forming </li></ul><ul><li>Surfactants </li></ul><ul><li>Stimulants </li></ul><ul><li>Osmotics </li></ul>
  17. 17. Bulk Forming Laxatives <ul><li>Absorb water </li></ul><ul><li>Soften and enlarge stool </li></ul><ul><li>Fecal swelling promotes peristalsis </li></ul><ul><li>methylcellulose (Citrucel ® ) </li></ul><ul><li>psyllium (Metamucil ® ) </li></ul><ul><li>Polycarbophil </li></ul>
  18. 18. Surfanctant Laxatives <ul><li>Lowers surface tension </li></ul><ul><ul><li>Facilitates water penetration </li></ul></ul><ul><li>Docusate salts </li></ul><ul><ul><li>Colace ® </li></ul></ul><ul><ul><li>Modane Soft ® ) </li></ul></ul>
  19. 19. Stimulant Laxatives <ul><li>Stimulate peristalsis </li></ul><ul><li>Increases water and electrolytes secretion into intestinal lumen </li></ul><ul><li>Decreases water and electrolyte reabsorption </li></ul><ul><li>Phenylolpthalein </li></ul><ul><ul><li>(Ex-Lax ® , Feen-a-Mint ® , Correctol ® ) </li></ul></ul><ul><li>bisacodyl (Ducolax ® ) </li></ul>
  20. 20. Osmotic Laxatives <ul><li>Poorly absorbed salts remain in fecal matter </li></ul><ul><li>Pull water into lumen </li></ul><ul><li>Magnesium hydroxid (Milk of Magnesia®) </li></ul>
  21. 21. Antidiarrheal <ul><li>Diarrhea is usually a compensatory action… </li></ul><ul><ul><li>Treatment aimed at cause, no symptom </li></ul></ul><ul><li>Opioid receptors in GI tract decrease motility </li></ul><ul><ul><li>Increase time for water reabsorbtion </li></ul></ul>
  22. 22. Antidiarrheal Agents <ul><li>paregoric/opium tincture </li></ul><ul><li>diphenoxylate (Lomotil ® ) </li></ul><ul><li>defenoxin (Motofen ® ) </li></ul><ul><li>loperamide (Imodium ® ) </li></ul>
  23. 23. Vomiting Stimulus
  24. 24. Antiemetics <ul><li>Serotonin (5HT) Antagonists </li></ul><ul><li>Dopamine (DA) Antagonists </li></ul><ul><li>Anticholinergics (muscarinic blockers) </li></ul><ul><li>Cannabinoids </li></ul>
  25. 25. Serotonin Antagonists <ul><li>Used to treat side effects of chemotherapy-induced emesis </li></ul><ul><li>condansetron (Zofran ® ) </li></ul><ul><li>Doesn’t affect dopamine receptors </li></ul><ul><ul><li> no extrapyramidal effects </li></ul></ul><ul><li>Granisetron (Kytril®) </li></ul>
  26. 26. Dopamine Antagonists <ul><li>Phenothiazines </li></ul><ul><ul><li>prochloraperazine (Compazine®) </li></ul></ul><ul><ul><li>promethazine (Phenergan®) </li></ul></ul><ul><li>Butyrophenones </li></ul><ul><ul><li>haloperidol (Haldol ® ) </li></ul></ul><ul><ul><li>droperidol (Inapsine ® ) </li></ul></ul><ul><li>metoclopramide (Reglan ® ) </li></ul>
  27. 27. Cannabinoids <ul><li>Tetrahydrocannabinol (THC) </li></ul><ul><ul><li>Active ingredient in marijuana </li></ul></ul><ul><ul><li>Dronabinol (Marinol ® ) </li></ul></ul><ul><ul><li>Nabilone (Cesamet ® ) </li></ul></ul>
  28. 28. Digestion Aids <ul><li>Useful for inactive vagal stimulus/bypassed duodenum </li></ul><ul><li>Pancreatin (Entozyme ® ) </li></ul><ul><li>Pancrelipase (Viokase ® ) </li></ul>
  29. 29. Topics <ul><li>Peptic ulcer disease/dyspepsia </li></ul><ul><li>GORD </li></ul><ul><li>Inflammatory bowel disease </li></ul><ul><li>Irritable bowel syndrome </li></ul><ul><li>Diarrhoea </li></ul><ul><li>Constipation </li></ul><ul><li>Pancreatitis </li></ul>www.freelivedoctor.com
  30. 30. Dyspepsia / Peptic ulcer disease <ul><li>Dyspepsia: upper abdo pain/discomfort </li></ul><ul><li>(fullness, bloating, distension, nausea) </li></ul><ul><li>Peptic ulcers </li></ul><ul><li>defects in mucosa extending through </li></ul><ul><li>muscularis mucosae </li></ul><ul><li>Prevalence </li></ul><ul><li>PUD 5-10% lifetime </li></ul><ul><li>dyspepsia 25-40% </li></ul><ul><li>Aetiology (most common) </li></ul><ul><ul><li>H.pylori </li></ul></ul><ul><ul><li>NSAIDs </li></ul></ul>www.freelivedoctor.com
  31. 31. www.freelivedoctor.com
  32. 32. Mucosa protective factors www.freelivedoctor.com
  33. 33. Parietal cell and acid regulation www.freelivedoctor.com
  34. 34. NSAIDs <ul><li>Antiinflammatory </li></ul><ul><li>Analgesic </li></ul><ul><li>Antipyretic </li></ul><ul><li>Chemically heterogeneous </li></ul><ul><li>Reversible competitive inhibitors of COX activity (Aspirin irreversible) </li></ul><ul><li>Reduce prostaglandin synthesis (COX-1) </li></ul><ul><ul><li>↓ Mucus </li></ul></ul><ul><ul><li>↓ bicarbonate </li></ul></ul><ul><ul><li>↓ blood flow </li></ul></ul><ul><ul><li>↓ proliferation of cells </li></ul></ul><ul><ul><li>↑ gastric acid secretion </li></ul></ul><ul><li>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 </li></ul><ul><li>Biliary excretion and reflux of metabolites into stomach </li></ul>www.freelivedoctor.com
  35. 35. Helicobacter pylori <ul><li>Peptic ulcers </li></ul><ul><li>Gastric carcinoma/lymphoma </li></ul><ul><li>Mucosal atrophy </li></ul><ul><li>Tests </li></ul><ul><ul><li>Urea breath test (sens. and spec. ~95%) </li></ul></ul><ul><ul><li>Endoscopic (urease, histology) </li></ul></ul><ul><ul><li>Stool antigen (sens. and spec. ~ 95%) </li></ul></ul><ul><ul><li>(serology) </li></ul></ul><ul><ul><li>Omit PPI for 2 weeks prior to tests </li></ul></ul>www.freelivedoctor.com
  36. 36. H. pylori www.freelivedoctor.com
  37. 37. Management of dyspepsia <ul><li>Therapeutic trial of acid suppressing medication </li></ul><ul><li>H. pylori screening </li></ul><ul><li>If alarm features </li></ul><ul><ul><li>GI bleeding </li></ul></ul><ul><ul><li>Unintentional weight loss </li></ul></ul><ul><ul><li>Progressive dysphagia </li></ul></ul><ul><ul><li>Odynophagia </li></ul></ul><ul><ul><li>Persistant vomiting </li></ul></ul><ul><ul><li>Iron deficiency anaemia </li></ul></ul><ul><ul><li>Mass/ suspicious barium meal </li></ul></ul><ul><li>Do Endoscopy </li></ul>Gastric ulcer www.freelivedoctor.com
  38. 38. Treatment <ul><li>Lifestyle advice </li></ul><ul><ul><li>Diet (alcohol, caffeine…) </li></ul></ul><ul><ul><li>Smoking </li></ul></ul><ul><li>Medication </li></ul><ul><ul><li>Stop NSAIDs if possible </li></ul></ul><ul><ul><li>H-2 receptor antagonists </li></ul></ul><ul><ul><li>Proton pump inhibitors </li></ul></ul><ul><ul><li>H. pylori eradication </li></ul></ul><ul><ul><li>Antacids </li></ul></ul><ul><ul><li>Misoprostol (NSAIDs) </li></ul></ul>www.freelivedoctor.com
  39. 39. H2 receptor antagonists <ul><li>Cimetidine, Ranitidine, Famotidine, Nizatidine </li></ul><ul><li>Competitive and selective inhibition of histamine H-2 receptor </li></ul><ul><li>Suppress 24 hr gastric secretion by 70% </li></ul><ul><li>Less effective than PPI </li></ul><ul><li>Caution: renal failure, pregnancy, breast feeding </li></ul><ul><li>Interaction: Cimetidine binds to CYP 450 (retards oxidative drug metabolism) </li></ul><ul><li>note interactions with warfarin, phenytoin, theophylline.. </li></ul><ul><li>Side effects </li></ul><ul><ul><li>Well tolerated, less than 3% adverse effects </li></ul></ul><ul><ul><li>Diarrhoea, headache, drowsy, fatigue, constipation, CNS, LFT </li></ul></ul><ul><ul><li>Rarely pancreatitis, bradycardia, AV block, confusion (elderly, especially cimetidine) </li></ul></ul><ul><ul><li>Rarely blood dyscrasias </li></ul></ul>www.freelivedoctor.com
  40. 40. Proton pump inhibitors <ul><li>Omeprazole, Lansoprazole, Pantoprazole, Esomeprazole, Rabeprazole </li></ul><ul><li>Prodrugs activated in acidic secretory canaliculi </li></ul><ul><li>Inhibit gastric H + K + ATPase irreversibly </li></ul><ul><li>Decrease acid secretion by up to 95% for up to 48 hours </li></ul><ul><li>Use: Ulcers, GORD, Zollinger-Ellison Syndrome, reflux oesophagitis </li></ul><ul><li>Side effects </li></ul><ul><ul><li>Generally well tolerated </li></ul></ul><ul><ul><li>mc Gastrointestinal, headache, headache dizziness </li></ul></ul><ul><ul><li>Omeprazole – impotence, gynaecomastia </li></ul></ul><ul><ul><li>May increase risk of GI infections (reduced acidity) </li></ul></ul><ul><li>Note: pH > 6 necessary for platelet aggregation </li></ul><ul><li>Give high dose PPI in active GI bleed (eg Omeprazole 8mg/hr for 72 hrs) </li></ul>www.freelivedoctor.com
  41. 41. H. pylori eradication <ul><li>Eradication increases ulcer healing </li></ul><ul><li>Reduces recurrence </li></ul><ul><li>MALT, Ca (can lead to resolution) </li></ul><ul><li>Triple therapy </li></ul><ul><li>For 7 (14) days twice daily eg </li></ul><ul><li>full dose PPI + </li></ul><ul><li>Amoxicillin + </li></ul><ul><li>Clarithromycin /Metronidazole </li></ul><ul><li>Effective in 80-85% </li></ul>www.freelivedoctor.com
  42. 42. Other <ul><li>Antacids </li></ul><ul><ul><li>Mg and Al hydroxides </li></ul></ul><ul><ul><li>May chelate other drugs (avoid concomitant administration of other drugs) </li></ul></ul><ul><ul><li>Side effects: diarrhoea (Mg), constipation (Al) </li></ul></ul><ul><ul><li>Milk alkali syndrome (alkalosis, renal insufficiency, hypercalcemia) </li></ul></ul><ul><li>Sucralfate </li></ul><ul><ul><li>Forms sticky polymer in acidic environment </li></ul></ul><ul><ul><li>Inhibits hydrolysis of mucous proteins by pepsin </li></ul></ul><ul><ul><li>1 g bd to 1g qds </li></ul></ul><ul><ul><li>SE: constipation, aluminium absorption (avoid in severe renal impairment due to risk of encephalopathy) </li></ul></ul>www.freelivedoctor.com
  43. 43. Misoprostol <ul><li>PGE1 analogue </li></ul><ul><li>Stimulates Gi pathway ( ↓cAMP and ↓gastric acid) </li></ul><ul><li>↑ blood flow and ↑ mucus and bicarbonate secretion </li></ul><ul><li>Use: prevention of NSAID induced injury </li></ul><ul><li>Side effects : diarrhoea, pain, cramps (30%) </li></ul><ul><ul><ul><li>Can cause exacerbation of IBD </li></ul></ul></ul><ul><li>Contraindication: pregnancy, caution in women of childbearing age </li></ul><ul><li> can induce labour! </li></ul>www.freelivedoctor.com
  44. 44. Nonvariceal Upper GI Bleed <ul><li>Resuscitate (iv access, fluids, catheter, transfusion) </li></ul><ul><li>Bloods (cross match, FBC, U & E, clotting) </li></ul><ul><li>Drugs </li></ul><ul><ul><li>Acid suppressing drugs (stabilize clot) </li></ul></ul><ul><ul><li>Somatostatin – reduces acid secretion and splanchnic blood flow </li></ul></ul><ul><ul><li>Antifibrinolytic drugs – tranexamic acid reduces need for surgery </li></ul></ul><ul><ul><li>and mortality </li></ul></ul><ul><li>+/- transfuse </li></ul><ul><li>Endoscopy: cause of bleeding, haemostasis (injection, clips, banding...), can usually wait until next day </li></ul>www.freelivedoctor.com
  45. 45. GORD <ul><li>Definition </li></ul><ul><li>Abnormal reflux of gastric contents into oesophagus </li></ul><ul><li>± mucosal damage </li></ul><ul><li>Prevalence </li></ul><ul><li>> 50% of population > once a year </li></ul><ul><li>50% of patients have erosive oesophagitis </li></ul><ul><li>Pathophysiology </li></ul><ul><li>Antireflux barrier (sphincter…) </li></ul><ul><li>Acid, pepsin, trypsin, bile acids, hiatus hernia </li></ul>www.freelivedoctor.com
  46. 46. Symptoms <ul><li>Heartburn </li></ul><ul><li>Belching </li></ul><ul><li>Asthma, cough </li></ul><ul><li>Hoarseness, sore throat, globus </li></ul><ul><li>Alarm features </li></ul><ul><li>GI bleeding </li></ul><ul><li>Unintentional weight loss </li></ul><ul><li>Progressive dysphagia </li></ul><ul><li>Odynophagia </li></ul><ul><li>Persistent vomiting </li></ul><ul><li>Iron deficiency anaemia </li></ul><ul><li>Mass/ suspicious barium meal </li></ul>www.freelivedoctor.com
  47. 47. Precipitants <ul><li>Food (fatty food, alcohol, caffeine) </li></ul><ul><li>Smoking </li></ul><ul><li>Obesity </li></ul><ul><li>Medication </li></ul><ul><ul><li>calcium antagonists, nitrates, theophyllines, NSAIDs, corticosteroids </li></ul></ul><ul><li>Pregnancy </li></ul><ul><li>Usually chronic relapsing course </li></ul>www.freelivedoctor.com
  48. 48. Diagnosis <ul><li>Symptoms </li></ul><ul><li>Empirical therapy </li></ul><ul><li>Endoscopy </li></ul><ul><ul><li>Failure of response to therapy </li></ul></ul><ul><ul><li>Alarm features </li></ul></ul><ul><ul><li>Barrett’s </li></ul></ul><ul><li>24-hour pH monitoring </li></ul><ul><ul><li>pH < 4 </li></ul></ul><ul><ul><li>Limited sensitivity </li></ul></ul>www.freelivedoctor.com
  49. 49. Complications <ul><li>Oesophagitis </li></ul><ul><li>Strictures, ulcers </li></ul><ul><li>Barrett ' s </li></ul>www.freelivedoctor.com
  50. 50. Barrett ' s <ul><ul><li>Intestinal columnar metaplasia </li></ul></ul><ul><ul><li>Malignant potential </li></ul></ul><ul><ul><li>Needs surveillance </li></ul></ul>www.freelivedoctor.com
  51. 51. Treatment <ul><li>Lifestyle advice </li></ul><ul><ul><li>Dietary habits (fat, alcohol, caffeine, timing) </li></ul></ul><ul><ul><li>Smoking </li></ul></ul><ul><ul><li>Weight loss </li></ul></ul><ul><ul><li>Raising head </li></ul></ul><ul><ul><li>But little evidence for all those </li></ul></ul><ul><li>Medication </li></ul><ul><ul><li>H-2 receptor antagonists </li></ul></ul><ul><ul><li>PPI </li></ul></ul><ul><ul><li>Antacids </li></ul></ul><ul><ul><li>Prokinetics </li></ul></ul>www.freelivedoctor.com
  52. 52. Inflammatory Bowel Disease <ul><li>Ulcerative colitis </li></ul><ul><ul><ul><li>Diffuse mucosal inflammation limited to the colon </li></ul></ul></ul><ul><li>Crohn 's disease </li></ul><ul><ul><ul><li>patchy transmural inflammation </li></ul></ul></ul><ul><ul><ul><li>May affect any part of GI tract </li></ul></ul></ul><ul><li>Features </li></ul><ul><ul><li>UC bloody diarrhoea, colicky pain, urgency, tenesmus </li></ul></ul><ul><ul><li>CD abdominal pain, diarrhoea, weight loss </li></ul></ul><ul><ul><li>intestinal obstruction </li></ul></ul><ul><ul><li>systemic symptoms </li></ul></ul>www.freelivedoctor.com
  53. 53. Drugs in IBD <ul><li>Aminosalicylates </li></ul><ul><li>Corticosteroids </li></ul><ul><li>Thiopurines </li></ul><ul><li>Methotrexate </li></ul><ul><li>Ciclosporin </li></ul><ul><li>Infliximab </li></ul>www.freelivedoctor.com
  54. 54. Aminosalicylates <ul><li>Sulfasalazine (5-aminosalicylic acid and sulfapyridine as carrier substance) </li></ul><ul><li>Mesalazine (5-ASA), eg Asacol, Pentasa </li></ul><ul><li>Balsalazide (prodrug of 5-ASA) </li></ul><ul><li>Olsalazine (5-ASA dimer cleaves in colon) </li></ul><ul><li>Oral, rectal preparation </li></ul><ul><li>Use </li></ul><ul><ul><li>Maintaining remission </li></ul></ul><ul><ul><li>Active disease </li></ul></ul><ul><ul><li>May reduce risk of colorectal cancer </li></ul></ul><ul><li>Adverse effects </li></ul><ul><ul><li>10 -45% </li></ul></ul><ul><ul><li>Nausea, headache, epigastric pain, diarrhoea, hypersensitivity, pancreatitis, blood disorders, lung disorders, myo/pericarditis </li></ul></ul><ul><ul><li>Caution in renal impairment, pregnancy, breast feeding </li></ul></ul>www.freelivedoctor.com
  55. 55. Corticosteroids <ul><li>Antiinflammatory agents for moderate to severe relapses </li></ul><ul><li>eg 40mg Prednisolone </li></ul><ul><li>Inhibition of inflammatory pathways ( ↓ IL transcription, suppression of arachidonic acid metabolism, lymphocyte apoptosis) </li></ul><ul><li>Side effects </li></ul><ul><ul><li>Acne, moon face, oedema </li></ul></ul><ul><ul><li>Sleep, mode disturbance </li></ul></ul><ul><ul><li>Dyspepsia, glucose intolerance </li></ul></ul><ul><ul><li>Cataracts, osteoporosis, myopathy… </li></ul></ul>www.freelivedoctor.com
  56. 56. Thiopurines <ul><li>Azathioprine, mercaptopurine </li></ul><ul><li>Inhibit ribonucleotide synthesis </li></ul><ul><li>Inducing T cell apoptosis by modulating cell signalling </li></ul><ul><li>Azathioprine metabolised to mercaptopurine and 6-thioguanine nucleotides </li></ul><ul><li>Use </li></ul><ul><ul><li>Active and chronic disease </li></ul></ul><ul><ul><li>Steroid sparing </li></ul></ul><ul><li>Side effects </li></ul><ul><ul><li>Leucopaenia (myelotoxic) </li></ul></ul><ul><ul><li>Monitor for signs of infection, sore throat </li></ul></ul><ul><ul><li>Flu like symptoms after 2 to 3 weeks, liver, pancreas toxicity </li></ul></ul>www.freelivedoctor.com
  57. 57. Methotrexate <ul><li>Inhibits dihydrofolate reductase </li></ul><ul><li>Probably inhibition of cytokine and eicosanoid synthesis </li></ul><ul><li>Use </li></ul><ul><li>Relapsing or active CD refractory or intolerant to AZA or Mercaptopurine </li></ul><ul><li>Monitor FBC, LFT </li></ul><ul><li>Side effects </li></ul><ul><ul><li>GI </li></ul></ul><ul><ul><li>Hepatotoxicity, pneumonitis </li></ul></ul>www.freelivedoctor.com
  58. 58. Ciclosporin <ul><li>Inhibitor of calcineurin, preventing clonal expansion of T cell subsets </li></ul><ul><li>Use </li></ul><ul><ul><li>Active and chronic disease </li></ul></ul><ul><ul><li>Steroid sparing </li></ul></ul><ul><ul><li>Bridging therapy </li></ul></ul><ul><li>Side effects </li></ul><ul><ul><li>Tremor, paraesthesiae, malaise, headache, abnormal LFT </li></ul></ul><ul><ul><li>Gingival hyperplasia, hirsutism </li></ul></ul><ul><ul><li>Major: renal impairment, infections, neurotoxicity </li></ul></ul><ul><li>Monitor </li></ul><ul><ul><li>Blood pressure, FBC, renal function </li></ul></ul>www.freelivedoctor.com
  59. 59. Infliximab <ul><li>Anti TNF- α monoclonal antibody </li></ul><ul><li>Potent anti inflammatory effects </li></ul><ul><li>Use </li></ul><ul><li>Fistulizing CD </li></ul><ul><li>Severe active CD refractory /intolerant of steroids or immunosuppression </li></ul><ul><li>iv infusion </li></ul><ul><li>Side effects </li></ul><ul><li>Infusion reactions </li></ul><ul><li>Sepsis </li></ul><ul><li>Reactivation of Tb, increased risk of Tb </li></ul>www.freelivedoctor.com
  60. 60. Principles of Managment of IBD <ul><li>Assess severity </li></ul><ul><li>Mild and distal </li></ul><ul><ul><li>topical steroids/aminosalicylates </li></ul></ul><ul><li>Diffuse or not responding – </li></ul><ul><ul><li>add oral steroids </li></ul></ul><ul><li>Severe </li></ul><ul><ul><li>admit, iv steroids, iv fluids, ?TPN etc </li></ul></ul><ul><li>Ulcerative colitis: </li></ul><ul><ul><li>Avoid antimotility drugs and antispasmodics as may precipitate paralytic ileus and megacolon </li></ul></ul>www.freelivedoctor.com
  61. 61. Medical management of UC <ul><li>Active left sided/extensive </li></ul><ul><ul><li>Aminosalicylate eg Mesalazine </li></ul></ul><ul><ul><li>Prednisolone 40mg (for prompt response or if mesalazine unsuccessful) – reduce dose gradually </li></ul></ul><ul><ul><li>Azathioprine for steroid dependant disease </li></ul></ul><ul><ul><li>Topical agents (rectal symptoms) </li></ul></ul><ul><ul><li>Ciclosporin for severe, steroid refractory colitis </li></ul></ul><ul><li>Active distal UC </li></ul><ul><ul><li>Mild/Mod topical mesalazine (or steroid) + oral mesalazine </li></ul></ul><ul><ul><li>+/- oral steroids </li></ul></ul>www.freelivedoctor.com
  62. 62. Severe UC <ul><li>Admission for iv therapy </li></ul><ul><li>Close monitoring </li></ul><ul><ul><li>Daily physical examination, regular vital signs, stool chart, CRP, AXR </li></ul></ul><ul><ul><li>FBC, ESR, CRP, U&E, albumin, LFT every 24-48 hours </li></ul></ul><ul><ul><li>Daily AXR if colonic dilatation (transverse >5.5cm) </li></ul></ul><ul><li>Therapy </li></ul><ul><ul><li>iv fluids and electrolytes if necessary </li></ul></ul><ul><ul><li>sc heparin (thromboembolism prophylaxis) </li></ul></ul><ul><ul><li>? Nutritional support </li></ul></ul><ul><ul><li>iv steroids </li></ul></ul><ul><ul><li>Withdrawal of antidiarrhoeal agents (can precipitate dilatation) </li></ul></ul><ul><ul><li>Aminosalicylates </li></ul></ul><ul><ul><li>Topical therapy </li></ul></ul><ul><ul><li>+/- surgical referral (colonic dilatation) </li></ul></ul><ul><ul><li>Stool frequency (>8) and CRP (>45) on day 3 predict need for surgery </li></ul></ul><ul><ul><li>Consider colectomy or iv ciclosporin </li></ul></ul>www.freelivedoctor.com
  63. 63. Medical Management of CD <ul><li>Assessment </li></ul><ul><ul><li>Site, pattern (inflammation, stricturing, fistulating), prior disease activity </li></ul></ul><ul><ul><li>Confirm disease activity (CRP, ESR) </li></ul></ul><ul><li>Active intestinal disease </li></ul><ul><ul><li>Mild – aminosalicylate </li></ul></ul><ul><ul><li>Mod/severe – oral corticosteroids (reduce gradually over 8 weeks) </li></ul></ul><ul><ul><li>Severe – iv steroids </li></ul></ul><ul><ul><li>Elemental/polymeric diets </li></ul></ul><ul><ul><li>TPN (fistulating) </li></ul></ul><ul><ul><li>Azathioprine as steroid sparing agent </li></ul></ul><ul><ul><li>Consider surgery </li></ul></ul><ul><li>Fistulating and perianal </li></ul><ul><ul><li>Metronidazole +/- ciprofloxacin </li></ul></ul><ul><ul><li>Azathioprine </li></ul></ul><ul><ul><li>Infliximab </li></ul></ul><ul><li>Other sites </li></ul>www.freelivedoctor.com
  64. 64. Maintenance of remission of CD <ul><li>STOP SMOKING </li></ul><ul><li>Mesalazine of limited benefit </li></ul><ul><li>Azathioprine effective but toxicity </li></ul><ul><li>Methotrexate </li></ul><ul><li>Infliximab </li></ul><ul><li>Steroid refractory disease </li></ul><ul><li>Definition </li></ul><ul><ul><li>Active disease on >20 mg prednisolone > 2 weeks </li></ul></ul><ul><ul><li>Relapse when dose reduction </li></ul></ul><ul><li>Azathioprine (monitor FBC) </li></ul><ul><li>MTX, Infliximab </li></ul>www.freelivedoctor.com
  65. 65. Constipation <ul><li>Stool: 70-85% water (100ml/d) </li></ul><ul><li>Normal stool frequency ≥ 3/week </li></ul><ul><li>Causes </li></ul><ul><ul><li>Dietary (fibre), drugs, hormonal disturbances, neurogenic disorders </li></ul></ul><ul><ul><li>systemic illnesses, IBS </li></ul></ul><ul><ul><li>colonic motility </li></ul></ul><ul><ul><li>disorder of defecation or evacuation (outlet) </li></ul></ul><ul><li>Management </li></ul><ul><ul><li>Diet, fluid, fibre rich diet </li></ul></ul><ul><ul><li>Avoidance of constipating drugs </li></ul></ul><ul><ul><li>Only then consider medication (haemorrhoids, exacerbation of angina from straining…) </li></ul></ul>www.freelivedoctor.com
  66. 66. Laxatives <ul><li>Bulk-forming </li></ul><ul><li>Stimulant </li></ul><ul><li>Faecal softeners </li></ul><ul><li>Osmotic laxatives </li></ul><ul><li>Bowel cleansing solutions </li></ul><ul><li>Oral </li></ul><ul><li>Rectal-suppositories, enemas </li></ul><ul><li>General Contraindications: intestinal perforation and obstruction </li></ul>www.freelivedoctor.com
  67. 67. Bulk-forming laxatives <ul><li>Increase faecal mass which stimulates peristalsis </li></ul><ul><li>Bulk/softness/hydration dependant on fibre </li></ul><ul><li>Ensure adequate fluid intake (obstruction) </li></ul><ul><li>Effect can be delayed by a few days </li></ul><ul><li>Try dietary fibre first! </li></ul><ul><ul><li>Wheat bran, oat bran, bran buiscuits </li></ul></ul><ul><ul><li>Pectins/hemicellulose (fruits, vegetables) </li></ul></ul><ul><li>Ispaghula (Fybogel, Isogel) </li></ul><ul><li>Methylcellulose (Cevelac) </li></ul><ul><li>Sterculia (Normacol) </li></ul><ul><li>Contraindication: intestinal obstruction, colonic atony, faecal impaction </li></ul><ul><li>Side effects: flatulence, abdominal distension, GI obstruction, rarely hypersensitivity </li></ul>www.freelivedoctor.com
  68. 68. Stimulant Laxatives <ul><ul><li>Increase intestinal motility </li></ul></ul><ul><ul><li>Diphenylmethane derivatives </li></ul></ul><ul><ul><li>Sodium picosulfate , hydrolyzed by bacteria to active form, effects vary </li></ul></ul><ul><ul><li>Bisacodyl (Dulco-lax), usually 5-10mg nocte </li></ul></ul><ul><ul><li>Anthraquinone Laxatives </li></ul></ul><ul><ul><li>Require activation in colon (bacteria), onset of action delayed (6-12 hours) </li></ul></ul><ul><ul><li>Senna ( Senokot), plant derivative </li></ul></ul><ul><ul><li>Danthron (Co-danthramer) possibly carcinogenic, only use in terminally ill </li></ul></ul><ul><ul><li>Docusate Sodium </li></ul></ul><ul><ul><li>stimulant and softening </li></ul></ul><ul><ul><li>Glycerol suppositories </li></ul></ul><ul><ul><li>(Parasympathomimetics such as bethanechol, neostimin rarely used) </li></ul></ul><ul><ul><li>Side effects: cramps, diarrhoea, hypokalaemia </li></ul></ul>www.freelivedoctor.com
  69. 69. Osmotic laxatives <ul><li>Osmotically mediated water retention </li></ul><ul><li>Nondigestible sugars and alcohols </li></ul><ul><ul><li>synthetic disaccharide, resists intestinal disacharidase </li></ul></ul><ul><ul><li>draw water in osmotically, not absorbed </li></ul></ul><ul><ul><li>Lactulose </li></ul></ul><ul><ul><li>Use: elderly, opioids, hepatic encephalopathy (↓ ammonia production) </li></ul></ul><ul><li>Magnesium salts </li></ul><ul><li>Phosphates (rectal, Fleet ) </li></ul><ul><li>Sodium citrate (rectal, Micralax Micro-enema ) </li></ul><ul><li>Polyethylene Glycol-Electrolyte Solutions - Macrogels </li></ul><ul><ul><li>Sequester fluid in bowel, poorly absorbed </li></ul></ul><ul><ul><li>Movicol </li></ul></ul>www.freelivedoctor.com
  70. 70. Faecal softeners - Emollients <ul><li>Sodium docusate (stimulant and softening) </li></ul><ul><li>Arachis oil enema for impacted faeces </li></ul><ul><li>Liquid Paraffin (oral solution) </li></ul><ul><li>Side effects: anal irritation, interference with absorption of fat soluble vitamins, granulomatous reactions </li></ul>www.freelivedoctor.com
  71. 71. Bowel cleansing solutions <ul><li>Before colonic surgery, colonoscopy and radiological examinations </li></ul><ul><li>eg Fleet, Klean-Prep, Picolax </li></ul><ul><li>Contraindications: obstruction, GI-ulceration, perforation, CCF, toxic colitis or megacolon, ileus </li></ul><ul><li>Side effects: nausea, bloating, cramps, vomiting </li></ul>www.freelivedoctor.com
  72. 72. Diarrhoea <ul><li>Definition </li></ul><ul><ul><li>Excessive fluid weight (200g/day) </li></ul></ul><ul><li>Mechanism </li></ul><ul><ul><li>Increased osmotic load </li></ul></ul><ul><ul><li>Excessive secretion (electrolytes and water) </li></ul></ul><ul><ul><li>Exudation of protein and fluid </li></ul></ul><ul><ul><li>Altered motility (rapid transit) </li></ul></ul><ul><ul><li>Often combined </li></ul></ul><ul><li>Management </li></ul><ul><li>Rehydration, maintain fluid and electrolyte balance </li></ul><ul><li>NaCl absorption linked with glucose uptake (rehydr. solutions) </li></ul><ul><li>Antimicrobial therapy. May mask clinical picture, delay clearance of organism, increase risk of systemic invasion. </li></ul>www.freelivedoctor.com
  73. 73. Antimotility drugs <ul><li>Opioids </li></ul><ul><ul><li>μ (motility) and δ (secretion) receptors, absorption (both) </li></ul></ul><ul><li>Loperamide – Imodium </li></ul><ul><ul><li>40-50x more potent than morphine </li></ul></ul><ul><ul><li>Poor CNS penetration </li></ul></ul><ul><ul><li>Increases transit time and sphincter tone </li></ul></ul><ul><ul><li>Antisecretory against cholera toxin and some E.coli toxin </li></ul></ul><ul><ul><li>T ½ 11 hours, dose: 4 mg followed by 2mg doses (16mg/d max) </li></ul></ul><ul><ul><li>Overdose: paralytic ileus, CNS depression </li></ul></ul><ul><ul><li>Caution in IBD (toxic megacolon) </li></ul></ul><ul><li>Codeine phosphate </li></ul><ul><li>Other </li></ul><ul><ul><li>Bismuth subsalicylate </li></ul></ul><ul><ul><li>Adsorbents such as Kaolin (not recommended), charcoal (insufficient data for adsorbents) </li></ul></ul>www.freelivedoctor.com
  74. 74. Diarrhoea <ul><li>Clostridium difficile </li></ul><ul><li>Clinical suspicion, test for toxins (stool) </li></ul><ul><li>Metronidazole PO </li></ul><ul><li>Vancomycin PO </li></ul>www.freelivedoctor.com
  75. 75. Irritable bowel syndrome <ul><li>Recurrent abdominal pain with disturbed bowel habits </li></ul><ul><li>9-12% of population affected </li></ul><ul><li>? Pathophysiology </li></ul><ul><li>Treatment </li></ul><ul><li>Dietary modification </li></ul><ul><li>Psychological therapies </li></ul><ul><li>Fibre – binding water (diarrhoea and constipation) </li></ul><ul><li>Antispasmodics </li></ul><ul><ul><li>Anticholinergic – Hyoscyamine, methscopolamine </li></ul></ul><ul><ul><li>Calcium channel antagonists and peripheral opioid receptor antagonists </li></ul></ul><ul><ul><li>Mebeverine: direct effect on smooth muscle cell </li></ul></ul><ul><li>Tricyclic antidepressants </li></ul><ul><li>Analgesic and neuromodulatory properties </li></ul><ul><li>Loperamide, codeine </li></ul>www.freelivedoctor.com
  76. 76. Antispasmodics <ul><li>Antimuscarinics </li></ul><ul><ul><li>Reduce motility </li></ul></ul><ul><ul><li>Quaternary amines </li></ul></ul><ul><ul><ul><li>eg hyoscine butylbromide (Buscopan) less lipid soluble and thus less well absorbed than atropine </li></ul></ul></ul><ul><ul><li>CI: angle-closure-glaucoma, mysthenia, paralytic ileus, pyloric stenosis and prostatic enlargement </li></ul></ul><ul><ul><li>SE: constipation, transient bradycardia, reduced bronchial secretions, urinary urgency etc </li></ul></ul><ul><li>Other </li></ul><ul><ul><li>Direct relaxants of intestinal smooth muscle </li></ul></ul><ul><ul><li>No serious side effects but avoid in paralytic ileus </li></ul></ul><ul><ul><li>Alverine </li></ul></ul><ul><ul><li>Mebeverine </li></ul></ul><ul><ul><li>Peppermint oil (Colpermin) </li></ul></ul>www.freelivedoctor.com
  77. 77. Pancreatitis <ul><li>Causes (mc) gallstones </li></ul><ul><li>alcohol </li></ul><ul><li>Diagnosis symptoms (abdominal pain, N&V) </li></ul><ul><li>pancreas enzymes (amylase, lipase) </li></ul><ul><li>USS +/- CT abdo </li></ul><ul><li>severity scores (APACHE) </li></ul><ul><li>Treatment rescuscitation (fluids + oxygen) </li></ul><ul><li>symptomatic control (analgesia) </li></ul><ul><li>prophylactic antibiotics if significant necrosis (30%) </li></ul><ul><li>?enteral nutritition </li></ul><ul><li>chronic pancreatitis: pancreatin eg Creon </li></ul>www.freelivedoctor.com
  78. 78. Liver and Drugs <ul><li>First pass metabolism in some drugs </li></ul><ul><li>Hepatic biotransformation </li></ul><ul><ul><li>Phase I: oxidation, reduction, hydrolysis </li></ul></ul><ul><ul><ul><li>Cytochrome P-450 system </li></ul></ul></ul><ul><ul><ul><li>Note: enzyme induction by eg rifampicin, carbamazepine, phenobarbitone, alcohol </li></ul></ul></ul><ul><ul><li>Phase II: conjugation to glucoronide, sulphate, glutathion, usually resulting in inactive compounds </li></ul></ul><ul><ul><li>Decrease lipid solubility and facilitate renal excretion </li></ul></ul><ul><ul><li>Export into plasma or bile -> excretion via GI tract or kidney </li></ul></ul><ul><li>Enterohepatic circulation (digoxin, morphine, …) </li></ul><ul><li>Most drugs lipophilic and thus crossing intestinal membranes </li></ul>www.freelivedoctor.com
  79. 79. Drug induced hepatotoxicity <ul><li>50% of causes of acute liver failure </li></ul><ul><li>Diagnosis </li></ul><ul><ul><li>History </li></ul></ul><ul><ul><li>Anorexia, nausea, fatigue </li></ul></ul><ul><ul><li>Jaundice </li></ul></ul><ul><ul><li>Blood tests </li></ul></ul><ul><ul><li>Rule out other causes (viral, alcohol…) </li></ul></ul><ul><ul><li>Overall rare </li></ul></ul><ul><ul><li>Importance of postmarketing surveillance to detect liver toxicity </li></ul></ul>www.freelivedoctor.com
  80. 80. Navarro, V. J. et al. N Engl J Med 2006;354:731-739 Liver Injury and Its Patterns www.freelivedoctor.com
  81. 81. Navarro, V. J. et al. N Engl J Med 2006;354:731-739 Key Guidelines in the Recognition and Prevention of Hepatotoxicity in Clinical Practice www.freelivedoctor.com
  82. 82. Navarro, V. J. et al. N Engl J Med 2006;354:731-739 Diagnosis of Drug-Related Hepatotoxicity www.freelivedoctor.com
  83. 83. Navarro, V. J. et al. N Engl J Med 2006;354:731-739 Key Elements of and Caveats in Assessing Cause in the Diagnosis of Drug-Related Hepatotoxicity www.freelivedoctor.com
  84. 84. Hoofnagle, J. H. et al. N Engl J Med 1997;336:347-356 Factors Predictive of a Sustained Beneficial Response to Interferon Alfa in Patients with Chronic Hepatitis www.freelivedoctor.com
  85. 85. References/further reading <ul><li>BNF </li></ul><ul><li>Harrison ‘s Principles of Internal Medicine </li></ul><ul><li>Pharmacology textbooks eg. Goodman&Gilman‘s </li></ul><ul><li>Nice Guidelines </li></ul><ul><li>Guidelines of the British Society of Gastroenterology </li></ul><ul><li>Review articles (NEJM, Lancet…) </li></ul>www.freelivedoctor.com
  86. 86. Test for H. pylori 2 H. pylori negative Gastric ulcer Full-dose PPI for 1 or 2 months Periodic review 6 Return to self care Stop NSAIDs , if used 1 Endoscopy 4 Healed Not healed Refer to specialist secondary care Low-dose treatment as required 5 Full-dose PPI for 2 months H. pylori positive, ulcer associated with NSAID use H. pylori positive, ulcer not associated with NSAID use Eradication therapy 3 Ulcer not healed, H. pylori negative Ulcer healed, H. pylori negative H. pylori positive Endoscopy and H. pylori test 4 Refer to specialist secondary care Flow chart for Mx of GU www.freelivedoctor.com Entry or final state Action Action and outcome
  87. 87. Test for H. pylori 2 Test negative Eradication therapy 3 Test positive, ulcer not associated with NSAID use Duodenal ulcer Full-dose PPI for 1 or 2 months Re-test for H. pylori 4 No response or relapse Negative Positive Low-dose treatment as required 6 Review 8 Response No response Eradication therapy 5 Response No response or relapse No response Exclude other causes of DU 7 Response Response Return to self care Stop NSAIDs , if used 1 Full-dose PPI for 2 months Test positive, ulcer associated with NSAID use Flow chart for Mx of DU www.freelivedoctor.com Entry or final state Action Action and outcome
  88. 88. Lauer, G. M. et al. N Engl J Med 2001;345:41-52 Characteristics of Hepatitis A Virus, Hepatitis B Virus, and Hepatitis C Virus www.freelivedoctor.com
  89. 89. Ganem, D. et al. N Engl J Med 2004;350:1118-1129 The Replication Cycle of HBV www.freelivedoctor.com
  90. 90. The Natural History of HCV Infection and Its Variability from Person to Person www.freelivedoctor.com
  91. 91. Lauer, G. M. et al. N Engl J Med 2001;345:41-52 Side Effects of Treatment with Interferon Alfa and Ribavirin www.freelivedoctor.com
  92. 92. Pathogen-Host Interactions in the Pathogenesis of Helicobacter pylori Infection www.freelivedoctor.com

×