Gi drugs outline


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  • Table 3. Factors Predictive of a Sustained Beneficial Response to Interferon Alfa in Patients with Chronic Hepatitis.
  • Table 3. Characteristics of Hepatitis A Virus, Hepatitis B Virus, and Hepatitis C Virus.
  • Figure 2. The Replication Cycle of HBV. HBV virions bind to surface receptors and are internalized. Viral core particles migrate to the hepatocyte nucleus, where their genomes are repaired to form a covalently closed circular DNA (cccDNA) that is the template for viral messenger RNA (mRNA) transcription. The viral mRNA that results is translated in the cytoplasm to produce the viral surface, core, polymerase, and X proteins. There, progeny viral capsids assemble, incorporating genomic viral RNA (RNA packaging). This RNA is reverse-transcribed into viral DNA. The resulting cores can either bud into the endoplasmic reticulum to be enveloped and exported from the cell or recycle their genomes into the nucleus for conversion to cccDNA. The small, peach-colored sphere inside the core particle is the viral DNA polymerase.
  • Figure 2. The Natural History of HCV Infection and Its Variability from Person to Person. The course of infection varies widely among persons. Factors that decrease the risk of progression include female sex and a younger age at infection; factors that increase the risk include alcohol intake, an older age at infection, male sex, and coinfection with other viruses. Persons with a favorable risk profile often do not have progressive liver disease until 30 or more years after infection. In contrast, 20 percent of persons with chronic hepatitis C will eventually have cirrhosis, and this can occur 20 years or less after infection, especially in those with alcohol abuse or coinfection with human immunodeficiency virus type 1 or hepatitis B virus. Once cirrhosis is established, the risk of hepatocellular carcinoma is 1 to 4 percent per year.
  • Table 2. Side Effects of Treatment with Interferon Alfa and Ribavirin.
  • Figure 2. Pathogen-Host Interactions in the Pathogenesis of Helicobacter pylori Infection. The host response to H. pylori participates in the induction of damage to the gastric epithelium and therefore has an integral role in H. pylori pathogenesis. During the early phase of the infection, binding of H. pylori to gastric epithelial cells, in particular through BabA and by strains harboring the cag pathogenicity island, results in the production of interleukin-8 and other chemokines, such as epithelial-cell-derived neutrophil-activating peptide 78 (ENA-78) and growth-related oncogene {alpha} (GRO-{alpha}), by epithelial cells. Nuclear factor-{kappa}B (NF-{kappa}B) and the early-response transcription-factor activator protein 1 (AP-1) are the intracellular messengers involved in this process. The chemokines secreted by epithelial cells bind to the proteoglycan scaffolding, generating a gradient along which polymorphonuclear cells (PMN) are recruited. The chronic phase of H. pylori gastritis associates an adaptive lymphocyte response with the initial innate response. Lymphocyte recruitment is facilitated by chemokine-mediated expression of vascular addressins such as vascular-cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) that are required for lymphocyte extravasation. Macrophages that participate in interleukin-8 production produce proinflammatory cytokines involved in the activation of the recruited cells, in particular T helper cells (Th0, Th1, Th2), that respond with a biased Th1 response to H. pylori. In turn, Th1-type cytokines such as interferon-{gamma} (INF-{gamma}) induce the expression of class II major histocompatibility complexes (MHC) and accessory molecules B7-1 and B7-2 by epithelial cells, making them competent for antigen presentation. The cytotoxin VacA- and Fas-mediated apoptosis induced by tumor necrosis factor {alpha} (TNF-{alpha}) leads to disruption of the epithelial barrier, facilitating translocation of bacterial antigens and leading to further activation of macrophages. Cytokines produced by macrophages can also alter the secretion of mucus, contributing to H. pylori-mediated disruption of the mucous layer. Cytokines produced in the gastric mucosa induce changes in gastric-acid secretion and homeostasis (dashed lines). TNF-{alpha}, interleukin-1{beta}, and interferon-{gamma} increase gastrin release, stimulating parietal and enterochromaffin cells and thus acid secretion. TNF-{alpha} also induces a decrease in the number of antral D cells, leading to decreased somatostatin production and indirectly enhancing acid production. LPS denotes lipopolysaccharide.
  • 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>
    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>
    31. 31.
    32. 32. Mucosa protective factors
    33. 33. Parietal cell and acid regulation
    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>
    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>
    36. 36. H. pylori
    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
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    49. 49. Complications <ul><li>Oesophagitis </li></ul><ul><li>Strictures, ulcers </li></ul><ul><li>Barrett ' s </li></ul>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    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>
    80. 80. Navarro, V. J. et al. N Engl J Med 2006;354:731-739 Liver Injury and Its Patterns
    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
    82. 82. Navarro, V. J. et al. N Engl J Med 2006;354:731-739 Diagnosis of Drug-Related Hepatotoxicity
    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
    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
    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>
    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 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 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
    89. 89. Ganem, D. et al. N Engl J Med 2004;350:1118-1129 The Replication Cycle of HBV
    90. 90. The Natural History of HCV Infection and Its Variability from Person to Person
    91. 91. Lauer, G. M. et al. N Engl J Med 2001;345:41-52 Side Effects of Treatment with Interferon Alfa and Ribavirin
    92. 92. Pathogen-Host Interactions in the Pathogenesis of Helicobacter pylori Infection
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