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Part IV Gasitrointesitinal disorders pharmacotherapy.pptx

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  1. 1. PART-IV Gastrointestinal Disorders Pharmacotherapy Kirubel Minsamo, BPharm, MSc. Assistant Professor of Clinical Pharmacy
  2. 2. Outline(Integrated Therapeutics) • Disease state definition • Epidemiology • Etiology and Review of relevant pathophysiology • Diagnosis • Clinical presentation • Goals of therapy • Pharmacotherapy • Monitoring and Evaluation
  3. 3. Gastrointestinal Disorders Pharmacotherapy I. Gastrointestinal Tract(GIT) Evaluation
  4. 4. Evaluation of the GIT: Introduction • GIT – Composed of organs and tissues that have diverse forms and functions – Esophagus, stomach, small intestine, large intestine, colon, rectum, biliary tract, gallbladder, liver, and pancreas • Patient history and physical examination remain important for initial assessment, triage • In addition diagnostic procedures are essential in the evaluation of GI disorders
  5. 5. Symptoms of Gastrointestinal Dysfunction • Heartburn, dyspepsia, abdominal pain, nausea, vomiting, diarrhea, constipation, and gastrointestinal bleeding • Signs and symptoms of malabsorption, hepatitis, and GI infection • Warning symptoms include : – weight loss, intractable vomiting, anemia, dysphagia, and bleeding – All clinicians should give due attention
  6. 6. Methods commonly used to assess pts with GI complaints • Include: –Careful patient's history –Comprehensive physical examination –Routine laboratory tests –Diagnostic studies and procedures
  7. 7. Patient History • Comprehensive pt history is the cornerstone • A clear, detailed, chronologic account of the patient's problems • Should include: – the onset of the problem – the setting in which it developed – factors that alleviate and aggravate the problem – its manifestations
  8. 8. Patient History….. • Lifestyle,…..diet and alcohol intake, use of medications, …(non-steroidal anti-inflammatory drugs) • Travel and potential exposure to infection is relevant • Pain or discomfort must be characterized and localized, and aggravating or relieving factors ascertained. • Altered bowel habit, particularly of recent onset, is significant, as is recent nausea, vomiting or anorexia (loss of appetite).
  9. 9. Patient History….. • Describe any vomitus and stool – haematemesis, stool black and tarry (shows upper GIT bleeding)…. stool fresh blood… (lower GIT bleeding) • Weight loss…. malabsorption, chronic inflammation or cancer • Liver, gallbladder, pancreas, stomach, small intestine and colon disorders ….vague, poorly localized symptoms. • Family history…. inflammatory bowel disease or colorectal cancer.
  10. 10. General Questions in a GI History • Tell me about the problem that you are experiencing. When did it start? What were you doing when the symptoms began? • Your pain location? Please point to the area where you feel pain. • How rapidly did the pain come on? Is your pain constant or intermittent? What factors exacerbate or alleviate your pain? Does the pain awaken you at night? • Have you had these symptoms in the past? • What medications are you taking to help alleviate the pain? How much do you take? Do these medications work? ……………………….
  11. 11. Drugs that May Cause GI Injury GI mucosal injury • Aspirin • Bisphosphonates • Chemotherapeutic agents • Corticosteroids • Iron preparations • NSAIDs • Pancreatic enzymes • Potassium chloride • Warfarin Jaundice • Androgens • Chlorpropamide • Corticosteroids • Erythromycin • Estrogens • Ethanol • Gold salts • Nitrofurantoin • Phenothiazines • Warfarin
  12. 12. Drugs that May Cause GI Injury Liver damage • Acetaminophen • Allopurinol • Amiodarone • Dapsone • Glyburide • Isoniazid • Ketoconazole • Lovastatin • Tetracycline • Valproic acid • Verapamil • Warfarin • Zidovudine • Methotrexate • Methyldopa • Monoamine oxidase inhibitors • Nevirapine • Nifedipine • Nitrofurantoin • Phenytoin • Propylthiouracil • Rifampin • Salicylates • Sulfonamides
  13. 13. Drugs that May Cause GI Injury Pancreatitis • Corticosteroids • Didanosine • Estrogens • Ethacrynic acid • Ethanol Pancreatitis cont’d…. • Opiates • Pentamidine • Sulfonamides • Tetracycline • Thiazides • Furosemide • Metronidazole
  14. 14. Physical Examination • A comprehensive evaluation of the patient should be performed General examination • Skin turgor (dehydration) • Skin and sclerae …pallor, jaundice and any rash. • Lymphadenopathy … node in the root of the neck, may indicate gastric cancer.
  15. 15. Physical Examination • A careful examination of the abdomen – Includes inspection, auscultation, percussion, and palpation in this order • Inspection: – may reveal scars, hernias, bulges, or peristalsis • Auscultation – mainly focused on analysis of bowel sounds and identification of bruits – should be performed prior to percussion and/or palpation
  16. 16. Physical Examination • Percussion of the abdomen – allows for detection of tympany, measurement of visceral organ size, and detection of ascites • Palpation – allow the clinician to identify tenderness, rigidity, masses, and hernias • Digital rectal examination – used to detect rectal masses and tenderness, and to assess muscle tone – Stool on the examiner's glove obtained subjected to testing for detection of occult blood
  17. 17. Laboratory and Microbiologic Tests • Used to – assess organ function – screen for certain GI disorders – evaluate the effectiveness of therapy • Should be viewed largely as supportive to an accurate history and physical examination – e.g. CBC, A serum chemistry panel • More specific lab blood tests can be done • Microbiologic and related studies are useful in evaluating patients – Stool examination
  18. 18. Laboratory and Microbiologic Tests Stool examination • Volume, consistency, colour and the presence of fat …..indicating malabsorption • Microscope ….parasites, ova or cysts and leucocytes or pus cells, which occur in dysentery or intestinal inflammation
  19. 19. Laboratory and Microbiologic Tests Blood Examination • Blood count: RBC, platelet and white cell count and red cell indices, levels of iron, ferritin, vitamin B12 and folic acid…..may be abnormal in malabsorption, inflammatory bowel disease, liver disease, PUD, intestinal cancer • Clotting tests: prolonged PT may indicate synthetic liver failure or vitamin K deficiency
  20. 20. Laboratory and Microbiologic Tests Liver chemistry: • Increased Alanine and aspartate transaminase level …liver cell damage and ….increased alkaline phosphatase (ALP) and ɣ-glutamyl transferase (ɣ GT) ….biliary tract disease • Inflammatory markers: Increased levels of C- reactive protein (CRP) and a raised erythrocyte sedimentation rate (ESR) may indicate inflammatory bowel disease (IBD), acute pancreatitis or infection. • Amylase and lipase levels: Acute pancreatitis causes massively raised amylase or lipase levels
  21. 21. Diagnostic studies and procedures • Radiology – Radiologic procedures rely on differential absorption of radiation of adjacent tissues to highlight anatomy and pathology • Two divisions – Non-computer assisted radiologic procedures – Computer assisted radiologic procedures
  22. 22. Non-computer assisted radiologic procedures  Upper GI Series Radiography – Refers to the radiographic visualization of the esophagus, stomach, and small intestine – Instruct pts to refrain from eating or drinking 8 to 12 hours prior to testing, which allows the upper GI tract to empty – contrast agent(Barium sulfate and/or gastrograffin) is administered to the patient at the beginning of the study – commonly uncovers gastric cancer, peptic ulcer disease, esophagitis, gastric outlet obstruction, and can be suggestive of Crohn's disease
  23. 23. Non-computer assisted radiologic procedures  Lower GI Series Radiography – used to examine the colon and rectum and is particularly useful if a colonic obstruction is suspected – Pts complaining of lower abdominal pain, constipation, or diarrhea are often referred for a lower GI series, also called a barium enema – Patient preparation • Instruct pts to refrain from eating or drinking 8 to 12 hours prior to testing • administering bowel-cleansing agents such as bisacodyl, magnesium citrate, magnesium hydroxide, or polyethylene glycol electrolyte (PEG) solution. – detect and evaluate enterocolitis, obstructions, volvulus, and mucosal and structural lesions
  24. 24. Computer assisted radiologic procedures • Imaging Studies – Frequently used imaging procedures for evaluating digestive disorders • Transabdominal ultrasonography • Computed tomography • Radionuclide scanning • Magnetic resonance imaging • GI tract endoscopy – used to examine the interior of a hollow viscus or canal
  25. 25. Gastrointestinal Disorders Pharmacotherapy II. Gastroesophageal Reflux Disease(GERD)
  26. 26. Case Studies • A 53-year-old man, who is otherwise healthy and has a 20-year history of occasional heartburn, reports having had worsening heartburn for the past 12 months, with daily symptoms that disturb his sleep • He reports having had no dysphagia, GI bleeding, or weight loss and in fact has recently gained 20 lb (9 kg) • What would you advise regarding his evaluation and treatment?
  27. 27. GERD: Introduction • Definition of GERD: – A condition that occurs when the refluxed stomach contents lead to troublesome symptoms and/or complications – Esophageal Vs Extraesophageal
  28. 28. GERD: Introduction • Esophageal GERD syndromes classified as – symptom-based or tissue injury based • Extraesophageal reflux syndromes – GERD symptoms associated with disease processes in organs other than the esophagus – Patients with extraesophageal reflux syndromes may present with reflux chest pain syndrome, laryngitis, or asthma(Atypical symptoms)
  29. 29. Epidemiology • GERD occurs in people of all ages – Most common in those older than age 40 years • No major difference b/n men and women except during pregnancy • Prevalence depends on geographic region • Important risk factors and co morbid conditions – Family history, obesity, smoking, alcohol consumption, certain medications and foods, respiratory diseases
  30. 30. Pathophysiology • Key factor in the development of GERD is – abnormal reflux of gastric contents from the stomach into the esophagus • Gastroesophageal reflux is associated with – defective lower esophageal sphincter (LES) pressure or function • Aggressive factors that damage esophagus up on reflux: – gastric acid, pepsin, bile acids, and pancreatic enzymes
  31. 31. Complications • Esophagitis • Esophageal strictures • Barrett esophagus • Esophageal adenocarcinoma • Esophageal bleeding – Use of NSAIDs drugs or Aspirin is an additional risk factor worsening of GERD complications
  32. 32. Clinical Presentation • Symptom-based esophageal GERD syndromes (with or without esophageal tissue injury) – Typical symptoms • Heartburn • Water brash (hypersalivation) • Belching • Regurgitation – Alarm symptoms (may be indicative of complications) – Dysphagia , Odynophagia
  33. 33. Clinical Presentation • Tissue injury–based esophageal GERD syndromes (with or without esophageal symptoms) – Symptoms (May present with alarm symptoms such as dysphagia, odynophagia or unexplained weight loss.) • Esophagitis • Strictures • Barrett esophagus • Esophageal adenocarcinoma
  34. 34. Clinical Presentation • Extraesophageal GERD syndromes – Symptoms (These symptoms have an association with GERD, but causality should only be considered if a concomitant esophageal GERD syndrome is also present.) • Chronic cough • Laryngitis • Asthma • Dental enamel erosion
  35. 35. Diagnostic tests for GERD • Clinical history • Barium radiography • Endoscopy • Ambulatory pH monitoring – Identifies patients with excessive esophageal acid exposure and helps determine if symptoms are acid related. • Empiric trial of a proton pump inhibitor as a diagnostic test for GERD
  36. 36. Treatment • Desired Outcomes – alleviate or eliminate the patient's symptoms – decrease the frequency or recurrence and duration of gastroesophageal reflux – promote healing of the injured mucosa, and – prevent the development of complications • Therapy is directed at : – augmenting defense mechanisms that prevent reflux and/or – decrease the aggressive factors that worsen reflux or mucosal damage
  37. 37. Therapeutic interventions in the mgt of GERD disease Pharmacologic interventions are targeted at improving defense mechanisms or decreasing aggressive factors (LES, lower esophageal sphincter).
  38. 38. Two approach: Pharmacotherapy • Step up approach: – Starting with noninvasive lifestyle modifications and patient-directed therapy and progressing to pharmacologic management or anti-reflux surgery • Step-down approach, – starting with a proton pump inhibitor given once or twice daily instead of an H2-receptor antagonist – and then stepping down to the lowest dose of acid suppression (either an H2-receptor antagonist or proton pump inhibitor) needed to control symptoms • Neither step up or down approach is superior
  39. 39. Evidence-Based Treatment Recommendations for GERD • Lifestyle modifications • Patient-directed therapy – Nonprescription antacids, H2-receptor antagonists, and PPIs (2 weeks limit if no response) for mild, infrequent heartburn/regur • Acid-suppression therapy – The preferred treatment for GERD – PPIs provide more rapid relief of symptoms and are more effective at healing the esophageal mucosa compared to H2RAs in patients with moderate to severe GERD • Promotility therapy (not as monotherapy) • Maintenance therapy – Most need continuous therapy to control sx and complications • Antireflux surgery
  40. 40. Fig: Algorithm for Management of gastroesophageal reflux disease. H2RA, H2-receptor antagonist; PPI, proton pump inhibitor.
  41. 41. Therapeutic Approach to GERD in Adults • Intermittent, mild heartburn – Lifestyle modifications plus – patient-directed therapy • Antacids: Maalox 30 mL as needed or after meals and at bedtime and/or • Nonprescription H2-receptor antagonists (taken up to twice daily): Cimetidine 200 mg or • Nonprescription proton pump inhibitor (taken once daily): Omeprazole 20 mg • If symptoms are unrelieved with lifestyle modifications and nonprescription medications after 2 weeks, patient should seek medical attention.
  42. 42. Therapeutic Approach to GERD in Adults • Symptomatic relief of GERD – Lifestyle modifications plus – Prescription-strength acid-suppression therapy • H2RA (for 6–12 weeks): Cimetidine 400 mg twice daily or • PPI(for 4–8 weeks): Omeprazole 20 mg once daily • Treat with maintenance dose if sx recurs, std dose of PPI or H2RA • Mild GERD can usually be treated effectively with H2RA • Patients with moderate to severe symptoms should receive a PPI as initial therapy
  43. 43. Therapeutic Approach to GERD in Adults • Healing of erosive esophagitis or treatment of patients presenting with moderate to severe symptoms or complications – Lifestyle modifications Plus – PPIs for 4–16 weeks (up to twice daily) Omeprazole 20 mg daily or – High-dose H2RA(for 8–12 weeks): Cimetidine 400 mg four times daily or 800 mg twice daily – For atypical or alarm symptoms, obtain endoscopy – Give a trial of a PPI. If symptoms are relieved, consider MT(maintenace therapy) – PPIs are the most effective MT for patients with atypical symptoms, complications, and erosive disease
  44. 44. Therapeutic Approach to GERD in Adults • Interventional therapies – Antireflux surgery • a viable maintenance alternative for select patients with well- documented GERD. – Endoscopic therapies • Patients not responding to pharmacologic therapy, including those with persistent atypical symptoms, should be evaluated to confirm the diagnosis of GERD
  45. 45. Gastrointestinal Disorders Pharmacotherapy III. PEPTIC ULCER DISEASE (PUD)
  46. 46. Learning Objectives  Recognize differences between ulcers induced by Helicobacter pylori, nonsteroidal anti-inflammatory drugs (NSAIDs), and stress-related mucosal damage (SRMD) in terms of risk factors, pathogenesis, signs and symptoms, clinical course, and prognosis.  Identify desired therapeutic outcomes for patients with H. pylori–associated ulcers and NSAIDinduced ulcers.  Identify factors that guide selection of an H. pylori eradication regimen and improve adherence with these regimens.  Determine the appropriate management for a patient taking a nonselective NSAID who is at high risk for ulcer-related GI complications (e.g., GI bleed) or who develops an ulcer.  Devise an algorithm for the evaluation and treatment of a patient with signs and symptoms suggestive of an H. pylori– associated or NSAID-induced ulcer. 48 2/8/2023
  47. 47. Case Study A 29 year old man presents with intermittent epigastric discomfort, without weight loss or evidence of GI-bleeding. He reports no use of aspirin or NSAIDs. Abdominal examination reveals epigastric tenderness. A serologic test for Helicobacter pylori is positive, and he receives a 10-day course of triple therapy (omeprazole, amoxicillin, and clarithromycin. Six weeks later, he returns with the same symptoms. How should his case be further evaluated and managed? 49 2/8/2023
  48. 48. Peptic Ulcer Diseases PUD refers to a defect in the gastric or duodenal mucosal wall that extends through the muscularis mucosa into the deeper layers of the submucosa. Duodenal Ulcer(DU):  Most common form of peptic ulcer  Located in the proximal duodenum  Incidence, death rates, need for surgery, and physician visits have decreased by 50% over the past 30 years.  Due to Eradication of H. pylori  Unlike to GU Malignant DUs are extremely rare 50 2/8/2023
  49. 49. Peptic Ulcer Diseases….. Gastric Ulcer(GU)  Less common than DU in absence of NSAIDs  Found distal to the junction b/n the antrum and the acid secretory mucosa  Occur later in life (peak incidence 6th decade)  Silent ……… presenting only after a complication  More than half occur in males PUD can also occur in the  Esophagus, secondery to GERD  Small bowel adjacent to gastroenteric anastomoses 51 2/8/2023
  50. 50. 52 2/8/2023
  51. 51. Epidemiology In the USA, PUD affects approximately 4.5 million people annually with lifetime prevalence estimated to be 11% to 14% in men and 8% to 11% in women. 53 2/8/2023
  52. 52. Etiology Multifactorial Two most common causes of PUD are: Helicobacter pylori infection ( 70-80%) Non-steroidal anti-inflammatory drugs (NSAIDS)  Others  Stressful situations  Smoking cigarettes  Alcohol  Genetic predisposition  Zollinger-Ellison syndrome  Medications: Corticosteroids, bisphosphonates, KCl, chemotherapeutic agents 54 2/8/2023
  53. 53. 2/8/2023 55 Effects of H. pylori on gastric Hormones
  54. 54. Mechanisms by which NSAIDs may induce mucosal injury 56 2/8/2023
  55. 55. 2/8/2023 57
  56. 56. 2/8/2023 58
  57. 57. Etiology: Others  Stress-Related Mucosal Damage  Physiologically stressful situations that lead to SRMD include sepsis, organ failure, prolonged mechanicalventilation, thermal injury, trauma, and surgery  Zollinger–Ellison Syndrome  A gastrin-secreting tumor or gastrinoma (Zollinger- Ellison syndrome) accounts for <1% of all PUs from uncontrolled acid production  Cigarette smoking is associated with a higher prevalence of ulcers in patients infected with H. pylori; however, it does not seem to increase the risk of recurrence once H. pylori has been eradicated 59 2/8/2023
  58. 58. Etiology: Others  Dietary factors such as coffee, tea, cola, alcohol, and a spicy diet may cause dyspepsia but have not been shown independently to increase PUD risk.  Medications: Corticosteroids, bisphosphonates, KCl, chemotherapeutic agents, etc 60 2/8/2023
  59. 59. Comparison of Common Forms of PUD 2/8/2023 61 Characteristi c H. pylori Induced NSAID Induced SRMD Condition Chronic Chronic Acute Site of damage Duodenum > stomach Stomach > duodenum Stomach > duodenum Intragastric pH More dependent Less dependent Less dependent Symptoms Usually epigastric pain Often asymptomatic Asymptomatic Ulcer depth Superficial Deep Most superficial GI bleeding Less severe, single vessel More severe, single vessel More severe, superficial mucosal capillaries
  60. 60. PUD: Pathophysiology PU develop as a result of imbalance between: Aggressive/Injurious factors e.g., gastric acid, pepsin, bile salts, pancreatic enzymes and Defensive factors maintaining mucosal integrity e.g., mucus, bicarbonate, blood flow, prostaglandins, growth factors, cell turnover 62 2/8/2023
  61. 61. Figure 2. Balance between injurious and protective factors in peptic ulceration. Injurious factors (on left-hand side) guide investigations; protective factors (on lower right-hand side) indicate possible treatment 63 2/8/2023
  62. 62. 2/8/2023 64
  63. 63. 2/8/2023 65
  64. 64. Diagnosis of PUD Diagnosis of ulcer either by upper GI radiography or upper endoscopy Diagnosis of H. Pylori  Non-invasive  C13 or C14 Urea Breath Test- best test for detection of active infection  Stool antigen test, H. pylori IgG titer (serology)  Invasive  Biopsy and Rapid Urease test  It should be ensured that patients undergoing a breath test, stool antigen test, or endoscopy are free from medication with PPIs or H2RAs for a minimum of 2 weeks and antibiotics for 4 weeks prior to testing 66 2/8/2023
  65. 65. Testing to Document H. Pylori Eradication Should be confirmed after end of therapy; noninvasive testing with UBT is preferred, 4-8 weeks after completion of therapy If ulcer recurs after eradication therapy, a more careful search for reinfection or eradication failure should be carried out by testing for presence of active infection (e.g. by histologic examination & culture, together with antibiotic- sensitivity test) 67 2/8/2023
  66. 66. PUD Treatment: Goal Rapid relief of symptoms Healing of ulcer Preventing ulcer recurrences Reducing ulcer-related complications Reduce the morbidity and mortality 68 2/8/2023
  67. 67. PUD Treatment: General Strategy Treat complications aggressively if present Determine the etiology of ulcer Discontinue NSAID use if possible Eradicate H. pylori infection if present or strongly suspected, even if other risk factors (e.g., NSAID use) are also present; Use antisecretory therapy to heal the ulcer if H. pylori infection is not present Approach to the patient presenting with ulcer- like symptoms. Next slide 69 2/8/2023
  68. 68. 2/8/2023 70
  69. 69. PUD Treatment: General Measures Lifestyle advice (e.g. diet, smoking, drinking) Alcohol, strong coffee or tea taken with moderation Late snacks are best avoided, b/c stimulate nocturnal gastric secretion. Inform Pts to avoid foods that provoke or aggravate Sxs Strongly discourage smoking and alcohol Warn pts against taking any medication : aspirin & NSAIDs Anxiety and stress should be reduced if possible 71 2/8/2023
  70. 70. PUD Treatment: Pharmacotherapy H2-Receptors antagonists Proton pump inhibitors Cyto-protective agents Prostaglandin agonists Antacids Antimicrobials for H. pylori eradication  Such as clarithromycin, metronidazole, amoxicillin 72 2/8/2023
  71. 71. Therapy of H. pylori Eradication  Recommended for HP-infected patients with GU, DU, ulcer-related complications First-line eradication therapy a) PPI–based, three-drug regimen containing two antibiotics  Usually clarithromycin and amoxicillin  Reserving metronidazole for back-up therapy (e.g., clarithromycin–metronidazole in penicillin-allergic patients)  PPI should be taken 30 to 60 minutes before a meal along with the two antibiotics.  Although treatment is minimally effective if used for 7 days, 10–14 days of treatment is recommended  Antisecretory drug may be continued beyond antimicrobial treatment in patients with a history of complicated ulcer (e.g., bleeding or in 73 2/8/2023
  72. 72. Therapy of H. pylori Eradication b) Quadruple therapy using a PPI (with bismuth, metronidazole, and tetracycline)  achieves similar eradication rates as PPI based triple therapy and permits a shorter treatment duration (7 days)  However, this regimen is often recommended as second-line treatment when a clarithromycin– amoxicillin regimen is used initially.  All medications except the PPI should be taken with meals and at bedtime. 74 2/8/2023
  73. 73.  If the initial treatment fails to eradicate HP, second- line empiric treatment should:  use antibiotics that were not included in the initial regimen  include antibiotics that do not have resistance problems  use a drug that has a topical effect (e.g., bismuth)  be extended to 14 days  Thus, if a PPI–amoxicillin–clarithromycin regimen fails, therapy should be instituted with a PPI, bismuth subsalicylate, metronidazole, and TTC for 14 days  Maintenance therapy with a PPI or H2RA is recommended for high-risk pts with  ulcer complications, pts who fail HP eradication, and 75 2/8/2023 Therapy of H. pylori Eradication
  74. 74. 2/8/2023 76
  75. 75. 2/8/2023 77
  76. 76. Treatment of NSAID-induced ulcers Nonselective NSAIDs should be discontinued (when possible) if an active ulcer is confirmed Most uncomplicated NSAID-induced ulcers heal with standard regimens of an H2RA, PPI, or sucralfate if the NSAID is discontinued If the NSAID must be continued, consideration should be given to reducing the NSAID dose or switching to acetaminophen, or a selective COX- 2 inhibitor PPIs are the drugs of choice when NSAIDs must be continued because potent acid suppression is required to accelerate ulcer healing. 78 2/8/2023
  77. 77. Treatment of NSAID-induced ulcers  If HP is present, treatment should be initiated with an eradication regimen that contains a PPI.  Patients at risk of developing serious ulcer-related complications while on NSAIDs should receive  prophylactic cotherapy with misoprostol or a PPI.  Patients with ulcers refractory to treatment should undergo upper endoscopy to confirm a nonhealing ulcer, exclude malignancy, and assess HP status  HP-positive patients should receive eradication therapy.  In HP negative pts, higher PPI doses (e.g., omeprazole 40 mg/day) heal the majority of ulcers.  Continuous PPI treatment is often necessary to maintain healing. 79 2/8/2023
  78. 78. 80 2/8/2023
  79. 79. Prevention of Stress-Related Mucosal Damage Prevention of stress ulcers involves maintaining hemodynamic stability to maximize mesenteric perfusion and pharmacologic suppression of gastric acid production. SUP is only indicated in intensive care unit (ICU) patients with certain risk factors Indications for stress ulcer prophylaxis include  Major trauma, major surgery, severe head trauma, multiple organ failure, burns covering more than 25% to 30% of body, severe sepsis, shock, mechanical ventilation, coagulopathy, and high- dose steroid use 81 2/8/2023
  80. 80. 2/8/2023 82
  81. 81. Long-Term Maintenance of Ulcer Healing Low-dose maintenance therapy with a PPI or H2RA is only indicated in  patients with severe complications secondary to PUD such as gastric outlet obstruction or  patients who need to be on long-term NSAIDs or high-dose corticosteroids and are at high risk for bleeding. 83 2/8/2023
  82. 82. Treatment of GI Bleeding  The immediate priorities in treating patients with a bleeding peptic ulcer are to achieve IV access, correct fluid losses, and restore hemodynamic stability.  Patients should be started on IV PPI therapy because optimal platelet aggregation, partially inhibited fibrinolysis, and better clot stabilization on the ulcer are achieved when the gastric pH is greater than 6.  IV PPI therapy should be continued for 72 hours because most rebleeding occurs during this time followed by oral PPI.  Three-day PPI infusion therapy has been shown to 84 2/8/2023
  83. 83. Treatment of Refractory Ulcers  Refractory ulcers are defined as ulcers that fail to heal despite 8 to 12 weeks of acid suppressive therapy  The presence of refractory ulcers requires a thorough assessment, including  evaluation of medication adherence,  extensive counseling and questioning regarding recent over-thecounter and prescription medication use, and  testing for H. pylori using a different method than previously done if testing was negative. 85 2/8/2023
  84. 84. Treatment of Refractory Ulcers  Treatment strategies  Changing from H2RA therapy to a PPI should be considered  esophagogastroduodenoscopy (EGD) with biopsy of the ulcer to exclude malignancy  H. pylori testing (if not done initially)  serum gastrin measurement to exclude ZES, and gastric acid studies  Increasing the starting dose of PPI therapy may heal up to 90% of refractory ulcers after 8 weeks of therapy 86 2/8/2023
  85. 85. Evaluation of Therapeutic Outcomes  Monitor pts for efficacy and safety of therapy  Ulcer pain typically resolves in a few days when NSAIDs are discontinued and within 7 days upon initiation of antiulcer therapy.  The persistence or recurrence of symptoms within 14 days after the end of treatment suggests failure of ulcer healing or HP eradication, or an alternative Dx such as GERD.  High-risk pts on NSAIDs should be closely monitored for signs and symptoms of bleeding, obstruction, penetration, and perforation  Follow-up endoscopy in pts with  frequent symptomatic recurrence, refractory disease, complications, or suspected hypersecretory states 87 2/8/2023
  86. 86. Gastrointestinal Disorders Pharmacotherapy IV. Viral Hepatitis
  87. 87. Patient case 89 C.R., a 28-year-old man, presents to the ED with jaundice, complaints of fatigue, and vague intermittent abdominal pain for the past month. C.R. was diagnosed with hepatitis B 2 years before admission. His social history includes IV drug abuse and alcohol abuse (none for 2 years). Several weeks ago, C.R. noted darkening of his urine and yellowing of his eyes.
  88. 88. Patient case… 90  Physical examination reveals a thin man in no apparent distress. He is afebrile, and his BP, HR, and RR are within normal limits. Moderate scleral icterus is noted. The abdomen is soft and non- distended. The liver is enlarged, and smooth with an edge palpable 5 cm below the costal margin  The spleen is palpable. The cardiac, pulmonary, neurologic, and extremity examinations all are within normal limits.
  89. 89. Patient case… 91 Lab test PT, 15.4 sec , INR, 1.8; AST, 326 U/L ; ALT, 382 U/L ; alkaline phosphatase, 142 U/mL ; total bilirubin, 4.2 mg/dL ; and albumin, 2.8 g/dL . Hepatitis serologic tests are positive for HBsAg, HBeAg, and anti-HBc and negative for IgM, anti-HBc, IgM anti-HAV, and anti-HCV. 1. What clinical findings does C.R. have that support the diagnosis of chronic hepatitis B infection? 2. Does C.R. require treatment for chronic hepatitis secondary to hepatitis B?
  90. 90. Cause of Hepatitis 92  Hepatitis: inflammation of liver; presence of inflammatory cells in organ tissue  Different causes  infectious (i.e, viral, bacterial, fungal, and parasitic organisms)  noninfectious (e.g, alcohol, drugs, autoimmune diseases)  A viral hepatitis is a inflammation of the liver due to viral infection called hepatitis virus  There are five main types of viral hepatitis: A, B, C, D, E
  91. 91. Acute and Chronic Hepatitis 93  Viral hepatitis can present as either an acute or chronic illness.  Acute hepatitis is an illness with a discrete date of onset with jaundice or increased serum aminotransferase concentrations >2.5 times the upper limit of normal.  Acute viral hepatitis infection is a systemic process and lasts as long as, but not exceeding, 6 months.  Chronic hepatitis is an inflammatory condition of the liver that involves ongoing hepatocellular necrosis for 6 months or more
  92. 92. Hepatitis virus transmission 94  Hepatitis A and E are typically caused by ingestion of contaminated food or water (feco- oral)…. shows acute hepatitis  Hepatitis B, C and D are typically caused by contact with contaminated blood or body fluids…..chronic hepatitis (cirrhosis and hepatic cancer)  Viral hepatitis types B and C together, are the most common cause of liver cirrhosis and cancer
  93. 93. Epidemiology 95  An estimated 57% of liver cirrhosis and 78% of liver cancer are due to hepatitis B virus (HBV and HCV infection  About 150 million people are chronically infected with HCV  Only 1 in 5 persons exposed to the hepatitis B and C virus develops acute symptoms, but chronic infection is common
  94. 94. Pathogenesis 96  Both direct and indirect, immune mediated responses instigated by the virus.  Direct cellular injury …..caused by the accumulation of intact virus or viral proteins.  Host cellular and humoral immune responses are linked to T lymphocytes, which enhance viral clearance from hepatocytes and cause liver injury host immune responses are more important than virologic factors in the pathogenesis of liver injury.
  95. 95. Diagnosis of hepatitis virus 97 Physical Exam  Low-grade fever  Significant vomiting and anorexia  tachycardia, dry mucous membranes, loss of skin turgor  Icteric phase: icterus of the sclerae or mucous membranes  The skin may be jaundiced and may reveal urticarial rashes.  Liver may be tender and diffusely enlarged with a firm, sharp, smooth edge.
  96. 96. Diagnosis… 98 Lab test Elevation of serum transaminases not diagnostic, but useful  ALT elevated more than AST  Acute Hepatitis: ALT > 1000  Chronic HCV: ALT is generally lower than 1000 Serum bilirubin: elevated…Bilirubin levels higher than 30 mg/dL indicate more severe disease.
  97. 97. Serologic evaluation 99  Because the clinical manifestations and incubation periods are similar among patients with hepatitis, serologies are useful in diagnosing the type of viral infection  Detecting specific;  antibodies against hepatitis A virus (anti-HAV),  hepatitis B surface antigen (HBsAg)  hepatitis C antibody (anti-HCV)  hepatitis B envelope antigen (HBeAg)  HBV-DNA  hepatitis D antibody (anti-HDV)
  98. 98. Hepatitis A 100  Mild self-limited disease and confers lifelong immunity to hepatitis A virus. Resolves with in 6 months  Transmission occurs primarily through the fecal– oral route.  Highest attack rates in 5-14 year olds….children serve as reservoir of infection  Symptoms and severity of HAV vary according to age. Children younger than 6 years of age typically are asymptomatic
  99. 99. 101 Prevalence of infection is related to the quality of the water supply, level of sanitation, and age.
  100. 100. Clinical manifestation 102  The host is usually asymptomatic during this stage of the infection  Older children and adults have symptomatic disease with jaundice occurring in >70% of cases.  Fatigue, weakness, anorexia, nausea, and vomiting.  Abdominal pain and hepatomegaly are common.  Less common symptoms include fever, headache, arthralgias, myalgias, and diarrhea.  Within 1 to 2 wks patients may enter an icteric phase with symptoms, including clay-colored stools, dark urine, scleral icterus, and jaundice.
  101. 101. Diagnosis: HAV 103  AST & ALT levels usually return to reference ranges over 5-20 weeks.  Serum Serology: presence of serum antigens and immunoglobins  Anti-HAV IgM : positive at the time of onset of symptoms; results remain positive for 3-6 months after the primary infection  Anti-HAV IgG appears soon after IgM and generally persists for many years….. indicative of previous exposure and immunity to HAV
  102. 102. Treatment and Prevention 104  Usually a self-limited disease that does not require a specific therapy.  Patients should abstain from alcohol during the acute phase of the disease  Potentially hepatotoxic medications should be avoided during the acute phase of the illness  Prophylaxis can be administered before (pre- exposure prophylaxis) or after exposure (post- exposure prophylaxis
  103. 103. Treatment and Prevention… 105 Immunoglobulin…passive immunization • Pre-exposure(travelers to intermediate and high HAV-endemic regions)….dose of 0.02 mL/kg of immunoglobulin administered intramuscularly confers protection for <3 months, and an IM dose of 0.06 mL/kg confers protection for 5 months. • Could be used for post-exposure prophylaxis but not later than 2 wks…. 0.02 mL/kg IM dose as soon as possible. Vaccine  Formulations of inactivated hepatitis A vaccine available (Havrix and Vaqta)  Programs have targeted children as the most effective means to control HAV.
  104. 104. Hepatitis B 106  Approximately 5% of the world’s population is infected with HBV.  It can occur in the form of chronic persistent hepatitis asymptomatic or chronic active hepatitis – symptomatic exacerbations of hepatitis  Causes Cirrhosis of Liver and Hepatocellular Carcinoma
  105. 105. 107
  106. 106. High Moderate Low/Not Detectable blood semen urine serum vaginal fluid feces wound exudates saliva sweat tears breastmilk Concentration of Hepatitis B Virus in Various Body Fluids 108
  107. 107.  Sexual: Sex workers and homosexuals are particular at risk.  Parenteral: IVDA, health workers are at increased risk.  Perinatal - Mothers who are HBeAg positive are much more likely to transmit to their offspring than those who are not. Hepatitis B Virus : Modes of Transmission 109
  108. 108. Clinical Manifestations 110  The clinical features of acute HBV infection are similar to those described for HAV infection….nausea, vomiting, anorexia, scleral icterus, and jaundice.  Extrahepatic manifestations, such as arthralgias, rash, edema  Complication  most significant complication of acute HBV infection is acute liver failure (onset of hepatic encephalopathy within 8 wks of the onset of symptoms)
  109. 109. 111 Serology evaluation of HBV I) HBsAg-- anti-HBs system  coating HBV  found in patients with acute or chronic HBV infection and chronic carriers.  Detectable 1 to 2 weeks after infection…. Persist for 1 to 6 wks in acute hepatitis  HBsAg can be found in : salive, urine, semina, tears, sweat and breast milk  HBsAb - used to document recovery and/or immunity to HBV infection.
  110. 110. Serology evaluation of HBV… 112 II) HBeAg  Appears shortly after HBsAg  Secreted product of the nucleocapsid core of HBV  Indicates viral replication and infectivity  Anti-HBe is a marker of reduced infectivity
  111. 111. Serology evaluation of HBV… 113 III) HBcAg—anti-HBc system  HBcAg can be found in the nuclei of liver cells, no free HBcAg in serum  HBcAg is the marker of replication of HBV  Anti-HBc IgM is a marker of acute infection and acute attack of chronic infection of HBV.  Anti-HBc IgG is the marker of past infection
  112. 112. Progression 114  Acute HBV Infection: 90% resolve by themselves; less than 1% develop fulminant hepatic failure  Chronic HBV Infection: 2-10% progress to chronic state  90% in children under five progress to chronic state  5% to 10% of people progress to HCC
  113. 113. Treatment 115  Progression of chronic hepatitis to cirrhosis is thought to be related to continued replication of the hepatitis B virus.  Seroconversion from HBeAg-positive to HBeAg- negative (with appearance of antiHBe), reductions in serum aminotransferase activity, elimination of circulating HBV DNA  The most effective agents for treating chronic hepatitis B have been interferons
  114. 114. Treatment …. 116 Interferon  Method of action is the inhibition of viral replication of cells thus assisting the immune system  Interferon alpha: SQ 5,000,000 U QD or 10, 000,000 U 3x weekly for 1 to 12 months. Peg interferon available…180 mcg weekly SQ
  115. 115. Treatment …. 117  Adverse effects associated with standard and PegIFN-a therapy are similar and quite common  Early side effects appear hours after administration and resemble an influenza-like syndrome with fever, chills, anorexia, nausea, myalgias, fatigue, and headache.  Resolve after repeated exposure  Late side effects that may necessitate dose reduction or discontinuation of therapy altogether.
  116. 116. Treatment …. 118  In addition to IFN-a several antiviral agents for treatment of chronic hepatitis B infection (lamivudine, adefovir, entecavir, and telbivudine) • Lamivudine –100 mg PO daily (anti HIV drug)  a nucleoside analogue reverse transcriptase inhibitor.  Well tolerated, most patients will respond favorably.  However, tendency to relapse on cessation of treatment, rapid emergence of drug resistance.
  117. 117. Prevention…per-exposure 119 Vaccination  The preferred vaccination schedule uses a three-dose regimen. The first dose is followed 1 month later by a second dose, and the third dose is administered 6 months after the initial dose.  Recipients of blood products, household and sexual contacts of HBV carriers, travelers to HBV-endemic areas, injecting drug users, all infants  Side effect is pain at the injection, Transient febrile, nausea, rash, headache,myalgias, and
  118. 118. Prevention…Post-exposure 120  Following exposure to HBV, prophylactic treatment with hepatitis vaccination and passive immunization with hepatitis B immunoglobulin (HBIG)  Percutaneous exposure: single dose of HBIG 0.06 mL/kg (3.4 mL) as an IM  Sexual contact: 0.06 mL/kg of HBIG as a single IM dose within 14days of the last exposure  Infants born to mothers who are HBsAg positive IM hepatitis B vaccine and HBIG (0.5 mL) within 12 hours of birth.
  119. 119. Hepatitis C 121  HCV causes both acute and chronic infection. Acute HCV infection is usually asymptomatic, and is only very rarely associated with life-threatening disease.  About 15–45% of infected persons spontaneously clear the virus within 6 months of infection without any treatment.  The remaining 55–85% of persons will develop chronic HCV infection…..Of those with chronic HCV infection, the risk of cirrhosis of the liver is between 15–30% within 20 years
  120. 120. 122  Highest incidence is among persons aged 20 to 39 years with a male predominance  HBV and HCV coinfection is common, results in more severe liver disease than infection with either virus alone, including increased risk of liver cancer
  121. 121. Transmission 123  Percutaneous Transmission  Blood transfusion (5-10%)  Injection drug users (48-90%)  Non-percutaneous transmission …transmission between sexual partners and from mother to child….. Less contagious
  122. 122. Clinical Manifestations 124  Most patients with acute HCV infection are asymptomatic.  Patients with chronic HCV infection generally complain of fatigue.  Nonspecific symptoms are similar to those seen with HBV infection, including nausea, anorexia, abdominal discomfort, and depression.
  123. 123. Diagnosis: HCV 125  Serum detection of Anti-HCV; cannot distinguish acute from chronic infection  Antibodies against core protein and nonstructural proteins; may appear 3 – 5 months after infection  Confirmed by qualitative HCV RNA (PCR) assay with a lower limit of detection of 50 IU/mL
  124. 124. Treatment 126  Acute infection: if early identification is possible, interferon therapy is rational.  Chronic active hepatitis.. Combination Peg interferon and oral daily dose of ribavirin.  Peginterferon alfa-2a.. 180 mcg SQ per week.  Ribavirin is given in divided daily doses (twice per day): the Ribavirin dose is 1000 mg for patients who weigh ≤75 kg or 1200 mg for those who weigh >75 kg.  Treatment with peginterferon plus ribavirin should be administered for 24 weeks in patients
  125. 125. Prevention 127 Pre-exposure Prophylaxis  No vaccines are effective against HCV Post-exposure Prophylaxis  Immunoglobulin is no longer recommended for post- exposure prophylaxis of hepatitis C infection because it is not effective  Others; Screening of blood, organ, tissue donors, High- risk behavior modification
  126. 126. Hepatitis D 128 Only as co-infection with acute HBV or with superinfection in chronic HBV carrier  Requires outer envelope of HBsAg for replication and transmission  Can progress to chronic disease  Incubation Period 30 to 150 days Serology  Hepatitis D antibody (Anti-HDV)  Ab not always present in acute infection---requires repeating the testing Risk Factors - Same high risk groups as those for HBV TX: IFN-alpha
  127. 127. Hepatitis E 129  Enterically transmitted infection; fecal-oral route, typically self-limited  Most outbreaks occur in developing countries.  Symptoms of acute hepatitis  Incubation period of hepatitis E virus is 2-9 weeks  Case fatality rate is 4%
  128. 128. Hepatitis E: diagnosis 130  Serum, liver, and stool samples can be tested for HEV RNA  Anti-HEV antibodies: IgM (acute) and IgG (chronic)  AST & ALT are elevated several days before the onset of symptoms; return to normal within 1-2 months after the peak severity of disease.  Treatment: supportive
  129. 129. Gastrointestinal Disorders Pharmacotherapy V. Cirrhosis and Portal Hypertension
  130. 130. Portal Hypertension and Cirrhosis: Introduction  Definition : Cirrhosis, or end-stage liver disease, defined as  a diffuse process characterized by fibrosis and a conversion of the normal hepatic architecture into structurally abnormal nodules  Results increased resistance to blood flow in portal hypertension and the development of varices and ascites  Hepatocyte loss and intrahepatic shunting of blood results in diminished metabolic and synthetic function, which leads to hepatic encephalopathy (HE) and coagulopathy 132
  131. 131. Portal Hypertension and Cirrhosis: Introduction  Clinical consequences of cirrhosis include  impaired hepatocyte function, increased intrahepatic resistance of portal hypertension, and hepatocellular carcinoma  Circulatory irregularities such as splanchnic vasodilation, vasoconstriction and hypoperfusion of the kidneys, water and salt retention, and increased cardiac output 133
  132. 132. Pathophysiology and Etiology  Cirrhosis results in  Elevation of portal blood pressure because of fibrotic changes within the hepatic sinusoids  Changes in the levels of vasodilatory and Vasoconstrictor mediators, and  An increase in blood flow to the splanchnic vasculature
  133. 133. Cont’d… patho  Fatty liver or steatosis from ethanol:  the first stage of liver injury - is characterized by lipid deposition in the hepatocytes  Steatosis is followed by liver inflammation (steatohepatitis), hepatocyte death, and collagen deposition leading to fibrosis  The specific mechanisms: not clear but suggestions  ethanol-induced oxidative stress on the liver
  134. 134. Consequences:  Cirrhosis and the pathophysiologic abnormalities that cause it result in  Ascites  Portal Hypertension  Esophageal varices  Hepatic encephalopathy, and  Coagulation disorders
  135. 135. Clinical Presentation: Sn and Sx  Anorexia, nausea, abdominal discomfort, weight loss, and malaise  Ascites, peripheral edema, jaundice, palmar erythema  Gynecomastia, testicle atrophy, amenorrhea, pubical hair lost  Hepatomegaly, spleenomegaly, encephalopathy, and bleeding
  136. 136. Laboratory Findings  Initially elevated ALT and AST level but at the end stage they can be normal or below normal  Elevated bilrubin most of the time  Low albumin level  Prolong prothrombin time (PT) and APTT  Elevated serum creatinine and blood urea nitrogen (BUN)  An elevation of prothrombin time was the single most reliable manifestation of cirrhosis.  The combination of thrombocytopenia, encephalopathy, and ascites had the highest predictive value.
  137. 137. Goal of therapy  The major goals of treating patients with cirrhosis include:  Slowing or reversing the progression of liver disease  Preventing superimposed insults to the liver  Preventing and treating the complications  Determining the appropriateness and optimal timing for liver transplantation
  138. 138. Portal Hypertension  Portal pressure is a function of flow and resistance to that flow across the hepatic vasculature  Normal portal pressure is below 6mmHg, and in cirrhotic patients may increase to 7 to 9mmHg  Portal hypertension:  results from both an increase in resistance to portal flow  increased intrahepatic resistance due on intrahepatic vasoconstriction, sinusoidal compression, and fibrosis  and also an increase in portal venous inflow  Caused by splanchnic vasodilation
  139. 139. Portal Hypertension and Varices  Portal pressure increases to 5 mmHg more than the pressure in the inferior vena cava  Development of varices and alternative routes of blood flow  Risk of varices when portal pressure exceed the vena cava pressure by > 12 mmHg  Hemorrhage from varices occurs in 25-40% of cirrhotic patients  Each episode of bleeding carries a 30% risk of death
  140. 140.  How Varices form  Portal hypertension causes blood flow to be forced backward, causing veins to enlarge and varices to develop across the esophagus and stomach from the pressure in the portal vein  The backup of pressure also causes the spleen to become enlarged
  141. 141. Management of varices  Involves three strategies:  Primary prophylaxis (prevention of the first bleeding episode);  Treatment of acute variceal hemorrhage; and  Secondary prophylaxis (prevention of rebleeding in patients who have previously bled)
  142. 142. Primary Prophylaxis  Nonselective Beta -Adrenergic Blockade(Propranolol or nadolol)  The mainstay of primary prophylaxis  reduce portal pressure by reducing portal venous inflow via two mechanisms:  a decrease in cardiac output through beta1- adrenergic blockade and a decrease in splanchnic blood flow through beta2- adrenergic blockade.  HR not less than 55 beats/min & SBP not less than 90 mm Hg  Adverse effects in 27% of patients  should be continued for life unless it is not
  143. 143. BB in Varices…cont’d  Only nonselective β-blockers :  have an adrenergic dilatory effect in mesenteric arterioles ---- decrease in portal blood circulation and pressure  Propanolol & Nadolol :  start: Propranolol 20 mg BID or 10 mg three times a day or nadolol 20 mg once daily  dose titration to a reduction in resting heart rate of 20% to 25%, an absolute heart rate of 55 to 60 beats/min, or the development of adverse effects.  Selective β-blockers (e.g., atenolol and metoprolol) have little effect on mesenteric arterioles  have not been shown to be effective in primary prophylaxis  Isosorbide-5-mononitrate: mentioned; alone vs with
  144. 144. Cont’d primary Px  Treatment Recommendations: Variceal Bleeding— Primary Prophylaxis  Prophylaxis therapy with a nonselective beta - adrenergic blocker  pts with small varices (< 5 mm) who have not bled & have no criteria for increased risk of bleeding ……controversy, most agree  Pts with small varices plus risk factors  medium to large varices (varices > 5 mm} & have not bled plus high risk factor  endoscopic variceal ligation can be used instead of BB
  145. 145. Acute Variceal Hemorrhage  An emergency and feared cxn of cirrhosis  Treatment goals include:  Volume resuscitation, acute treatment of bleeding, and prevention of recurrence of variceal bleeding  Replenishment of blood volume and correction of coagulopathy must be done with packed erythrocytes (to increase Hb concentration to 10 g/dL) and fresh frozen plasma and platelets  Protection of airway from aspiration of blood  Antibiotics to prevent SBP and G-ve systemic infection  Control of bleeding  Prevention of rebleeding, and preservation of liver function
  146. 146. Drug therapy: Acute variceal Bleeding  Drug Therapy  Drugs employed to manage acute variceal bleeding include:  The somatostatin analogue octreotide or vapreotide and  Vasopressin, terlipressin,  Work as splanchnic vasoconstrictors, thus decreasing portal blood flow and pressure  Endoscopic Therapy may be indicated  Endoscopic variceal band ligation (EVL)
  147. 147. Drug therapy: Acute variceal Bleeding [2]  Infection Prophylaxis—Short-Term Antibiotics  Norfloxacin 400 mg BID for 7 days Vs no treatment controls: Norfloxacin group  had a significantly lower incidence of SBP  No significant difference was seen in mortality  Guidelines recommend: 7 days of antibiotic prophylaxis for prevention of SBP in patients with variceal hemorrhage with oral norfloxacin (400 mg BID) or ciprofloxacin IV (400 mg BID) if P.O. no possible  Ceftriaxone IV (1 g/day) for 7 days : FQ resistance high
  148. 148. Secondary Prophylaxis/Prevention of Rebleeding  Secondary Prophylaxis: Prevention of Rebleeding  Prevent a recurrence of bleeding if survived first episode of bleeding  Combination therapy with beta-adrenergic blockers and chronic EVL : best option  Combo : BB + ISDN : unable to undergo EVL  initiation of β-blockers be delayed until after recovery of the initial variceal hemorrhage  Block the patient’s acute tachycardia if pt hypotension  Initiate: pt has had no bleeding for at least 24
  149. 149. Ascites and Spontaneous Bacterial Peritonitis  Ascites is the accumulation of fluid within the peritoneal cavity  Most common complication of cirrhosis  Spontaneous bacterial peritonitis (SBP)  is an infection of preexisting ascitic fluid without evidence for an intra-abdominal secondary source such as a perforated viscus  SBP is almost always seen in
  150. 150. Ascites mgt  Goals of therapy  To mobilize ascitic fluid  To diminish abdominal discomfort, back pain, and difficulty in ambulation  To prevent major complications  Non pharmacological management  Na+ and water restriction, therapuetic paracentesis  Pharmacological management  Diuretics  Combination of spironolactone and furosemide
  151. 151. 155 Approach to the patient with Ascites and SBP
  152. 152. Diuretics Therapy: Ascites Diuretics Therapy: Choice of agent  High level of circulating aldosterone  Decrease execration and increase production  Activation of RAS  hepatic impairment prolongs the half life of aldosterone  Low concentration of albumin  Spironolactone is rational choice  Dose 100 mg to 200 mg up to 400 mg  Combination with other diuretics, Furosemide  Spironolactone to furosemide ratio (100 : 40 mg)  Can be increased every 3 to 5 days simultaneously keeping ratio
  153. 153. Ascite Rx cont’d…  Monitoring: diuretic therapy  Triamterene and amiloride : alternative to spironolactone if intolerable side effects  goal is a weight loss of 0.5 to 1 kg/day  net fluid volume loss of about 0.5 to 1 L/day  If presented with both edema and ascites : initial fluid loss of up to 1 L/day would be reasonable  Diuresis > 0.5 to 1 kg/day (0.5–1 L) : associated with volume depletion, hypotension, and compromised renal function  Monitoring fluid intake and urine output  urine output should exceed fluid intake by about 300 to 1,000 mL/day
  154. 154. Diuretic Complications and Management  Initiate: with single morning doses of spironolactone 100 mg and furosemide 40 mg administered orally  Titrate diuretic therapy every 3 to 5 days using the 100 mg:40 mg ratio to attain adequate natriuresis and weight loss  reasonable daily weight loss goal is 0.5 kg  Maximum daily doses are 400 mg spironolactone and 160 mg furosemide….. maintains normokalemia  D/C diuretic: experience uncontrolled or recurrent encephalopathy, severe hyponatremia, renal insufficiency
  155. 155. Cxn…cont’d..  Electrolyte And Acid-base Disturbances  Hyponatremia, hyperkalemia, metabolic alkalosis  Hyponatremia : temporary withdrawal of diuretics and free water restriction  Hyperkalemia [in refractory ascites and impaired renal function requiring high doses of spironolactone]  Decreasing or holding spironolactone depending on renal function and serum potassium  Metabolic alkalosis [hypokalemia] : Furosemide can be temporarily withheld
  156. 156. Drug therapy: SBP  SBP  >92% of all cases of SBP are monomicrobial, with Escheria coli (the most common isolate),Klebsiella species, Other G-ve bacteria  G+ve organisms, Streptococcal (25%)  Anaerobic infection (rare <5%)  Consider antibiotic coverage for these condition  Third-generation cephalosporin : DOC for SBP  Prophylaxis against SBP  Short-term antibiotic prophylaxis should be used for 7 days to prevent SBP in cirrhosis patients with gastrointestinal hemorrhage  Patients who survive an episode of SBP should receive long-term prophylaxis with either daily norfloxacin or
  157. 157. SBP: Px…..cont’d..  Indications of Prophylaxis of Spontaneous Bacterial Peritonitis
  158. 158. Hepatic Encephalopathy (HE)  Hepatic encephalopathy is a neuropsychiatry syndrome caused by liver disease  The principles of mgt are  To treat or remove precipitating causes  To reduce or eliminate protein intake and  To suppress production of neurotoxins by bacteria in the bowel  The mainstay of therapy of HE involves measures to lower blood ammonia concentrations and includes diet therapy, lactulose, and antibiotics alone or in combination with lactulose  Lactulose (15-30 ml 8-hourly) administration lowers ammonia levels in the blood in several ways
  159. 159. HE… cont’d…  Lactulose lowers ammonia levels in the blood  creation of a laxative effect  reduces the time period available for ammonia absorption  leaching of ammonia from the circulation into the colon  increasing bacterial uptake of ammonia by colonic bacteria  reducing ammonia production by the small intestine  By interfering directly with the uptake of glutamine by the intestinal wall and its
  160. 160. HE… Rx…cont’d…  Metronidazole or Neomycin : inhibiting the activity of urease-producing bacteria  decrease production of ammonia  Metronidazole initiated at 250 mg twice daily but titrated up to four times daily  should not be considered first-line therapy  Indicated: who have not responded to diet and lactulose therapy & if deemed necessary for improved outcome  Rifaximin 400 mg three times daily provides similar effectiveness with less risk  Zinc replacement: decreasing ammonia levels and improving symptoms of HE
  161. 161. Evaluation of Therapeutic Outcomes  Monitoring Parameter  Ascites  Daily assessment of weight  Spontaneous bacterial peritonitis  Evidence of clinical deterioration (e.g., abdominal pain, fever, anorexia, malaise, fatigue)  Variceal bleeding  Child-Pugh score, endoscopy, CBC, evidence of overt bleeding  Hepatic encephalopathy  Grade of encephalopathy, EEG, psychological testing, mental status changes, concurrent drug therapy
  162. 162. Gastrointestinal Disorders Pharmacotherapy VI. Pancreatitis
  163. 163. Pancreatitis
  164. 164. Patient case #1 168  A 49-year-old man was admitted with a nine-month history of intermittent attacks of epigastric pain, jaundice and fever. These attacks usually last up to several days associated with nausea and vomiting. He was well in between attacks and had no loss of weight  What is likely diagnosis for this patients?
  165. 165. s 169 Function of the pancreas is to release digestive enzymes and insulin and glucagon . Ampull a of Vater
  166. 166. Body –Forms shell for stomach to rest upon. The Pancreas 170
  167. 167. Definition 171  Pancreatitis is an inflammation of the pancreas  Two forms:  Acute pancreatitis  Sudden…...mild to sever  often non-reoccurring …..90% self-limiting and resolves in a wk  Do not progress to chronic form  Chronic Pancreatitis  ongoing occurrence of inflammation  marked by ON and OFF abdominal pain
  168. 168. Epidemiology 172  300,000 case annually in US  10-20% are severe  Biliary and alcoholic cases account 90% ….biliary pancreatitis being the most prevalent type.  Incidence among AIDS patients 4-22%  Incidence ……..increase w/ age.  Onset in the first decade suggests ….a hereditary cause, infection (e.g., mumps), or trauma.
  169. 169. Etiology - I GET SMASHED… 173 I -idiopathic………no etiology is identified G -gallstone…..Gallstones may get stuck in the Ampulla of Vater causing to backflow then into pancrease E -ethanol (alcohol)….60-90% of patients have a history of alcohol abuse…. Second next to gall stone for acute case T -trauma S -steroids M -mumps and other viruses (Epstein-Barrvirus, Cytomegalovirus)
  170. 170. 174
  171. 171. Etiology - I GET SMASHED… 175  A -autoimmune disease (Systemic lupus erythematosus)  S -scorpion sting (e.g. Tityus trinitatis), and also snake bites  H-hypercalcemia, hyperlipidemia and hypotermia  E - Endoscopic Retrograde Cholangio- Pancreatography………a procedure that combines endoscopy and fluoroscopy  D -Drugs………….four categories
  172. 172. Etiology - I GET SMASHED… 176 Four Categories……………..drugs account for 2% incidence  Drugs that exacerbate high triglycerides  Estrogens, steroids, isotretinoin, hydrochlorothiazide, furosemide, and protease inhibitors  Drugs that cause hypersensitivity  Aminosalicylates, tetracycline, azathioprine, TMP/SMX, or ACEI  Drugs that have a toxic effect  Valproic acid, statins, sulindac, metformin, and didanosine  Drugs that cause pancreatic spasm.  Opiates and octreotide are thought to cause spasms of the sphincter of Oddi
  173. 173. Pathophysiology 177 • The events that initiate an inflammatory process are still NOT well understood • Trypsinogen- (a proteolytic enzyme)is normally released into the small intestine, where it is activated to trypsin • Acute pancreatitis involves premature activation of trypsinogen in to trypsin with in the pancreas, leading to activation of other digestive enzymes and autodigestion of the gland
  174. 174. Clinical manifestation#1 178  Abdominal pain:  may be continuous, intermittent or absent  Pattern is often atypical  RUQ or LUQ of the back  Diffuse throughout upper abdomen  Typical form:  Persistent , deep-seated,  Unresponsive to antacids  Worsened by alcohol intake or a heavy meal (especially fatty foods)  Often need narcotics  Acute pancreatitis related to alcohol occur …..one to three days after cessation of drinking.
  175. 175. Clinical manifestation#2 179  Nausea and vomiting  Incidence………90 percent of patients  Duration……….may persists for many hours  Associated symptoms………. Restlessness, agitation, and relief on bending forward  Patients with fulminant attacks may …… present in shock or coma.  Painless disease….in only………….5 to 10%  Most the pain is severe……….Emergency department visit and hospital admission is required
  176. 176. Clinical manifestation #3 180  Pancreatic insufficiency  Weight loss  Fat malabsorption:  Steatorrhea: 15% of patients present with steatorrhea and no pain… occur in chronic pancreatitis(>90% of pancreas is lost)  Pancreatic diabetes:  Like DM1 needs insulin
  177. 177. Complications 181  Necrotizing pancreatitis…….when pancreatic cell die  Leads to cyst or pocket like space  May lead into leakage of fluid containing toxins and enzymes leaks from the pancreas through the abdomen. This can damage blood vessels and lead to internal bleed  Respiratory Complications – due to irritation of diaphragm  shallow breathing  inflammatory exudates, and dyspnea
  178. 178. Complications 182  Ecchymotic discoloration of the flanks …….  the escape of blood into the tissues from ruptured blood vessels Grey-Turner's sign .  Bruise like …….b/n ribs and hip bones  The periumbilical region (Cullen's sign) ….  Retroperitoneal bleeding in patients with pancreatic necrosis.  Incidence: 1%......They reflect intra-abdominal hemorrhage - a poor prognosis.
  179. 179. Cullen’s sign 183
  180. 180. Grey Turner’s sign 184
  181. 181. Chronic pancreatitis 185  Chronic pancreatitis results from long standing inflammation leading to irreversible parenchymal destruction leading to pancreatic dysfunction  Chronic alcohol consumption , especially heavy drinking remain leading cause  Leads to………Persistent, recurrent episodes of severe pain  Symptoms;  Anorexia, nausea  Constipation, flatulence  Steatorrhea  Diabetes
  182. 182. Prognosis 186  The overall mortality rate……..10-15%  May be as high as…………..30%  Patients with biliary pancreatitis tend to………  have a higher mortality rate than patients with alcoholic pancreatitis.  In the first week of illness……………….most deaths result from multi-organ system failure.  In subsequent weeks………………….infection plays a more significant role
  183. 183. Diagnosis#1 187 Physical exam  Palpable epigastric mass - pseudocyst  Less common features:  subcutaneous nodular fat necrosis (panniculitis),  thrombophlebitis in the legs, and polyarthritis.  Fat necrosis lesions……0.5 to 2 cm  tender red nodules, located over the distal extremities but may occur elsewhere.
  184. 184. 188 Laboratory Evaluation/ Pancreatic enzymes  Early in the course of acute pancreatitis……..  there is a breakdown in the synthesis-secretion coupling of pancreatic digestive enzymes  i.e synthesis continues while there is a blockade of secretion.  As a result………….  digestive enzymes leak out of acinar cells through the basolateral membrane to the interstitial space and….then the systemic circulation. Diagnosis #2
  185. 185. Diagnosis#3 189  Amylase…Nonspecific !!!  Amylase levels > 3x normal very suggestive of acute pancreatitis  May be Normal in chronic pancreatitis!!! Enzyme level  severity  False (-)……..EtOH…………..or …………….Hyper- TG  False (+) …….renal failure, other abdominal or salivary gland process, acidemia
  186. 186. Diagnosis#4 190 Serum amylase (70-200 u/mL)  Is the most frequently ordered test to diagnose acute pancreatitis.  Rises within …6 to 12 hours of onset  Cleared fairly rapidly from the blood  half-life 10 hours  In uncomplicated attacks………..  serum amylase is usually elevated for three to five days.
  187. 187. Diagnosis#5 191 Serum Lipase (0 – 160 U/mL)  Less frequently ordered than amylase b/s…...Difficult to perform and lacked precision  Inclusion of co-lipase in the assay of commercially available kits has improved… diagnostic accuracy.  Sensitivity…………85 to 100 percent  However………..nonspecific elevations of lipase have been reported in almost as many diseases as amylase.
  188. 188. Diagnosis#6 192  Other inflammatory markers will be elevated  ALT > 3x normal  gallstone pancreatitis  96% specific but …………only 48% sensitive  Depending on severity may see:   Ca WBC   Hct BUN  glucose  Bilirubin…..25% pancreatic edema leads to compression of the bile duct
  189. 189. Diagnosis#7 193 Radiographic Evaluation  US or CT  show enlarged pancreas with stranding, abscess, fluid collections, hemorrhage, necrosis or pseudocyst  MRI…………..the newest  Better visualization of fluid collections  Endoscopic/Ultrasonography …………  even newer but used less  Useful in obese patients
  190. 190. Management 194  Supportive care is very important part of the management  Control of Pain……..Narcotic analgesics  Maintain Fluid/electrolyte balance  Correction of malabsorption with ………….adequate enzyme replacement and nutrition  Remove offending agent ………..if possible
  191. 191. Non-pharmacological#1 195  No oral food ………….until pain free…..pancreatic rest  Avoid fatty food to decrease pancreatic stimulation  Nasojejunal suction for patients with emesis  TPN may be needed  Aggressive volume repletion with IVF  Keep an eye on fluid balance/sequestration and electrolyte disturbances  Avoidance of alcohol/other offending agents  Prevention of Shock – hemodynamic stability * Administer Blood, Plasma expanders, Albumin
  192. 192. Non-pharmacological #2 196 Treatment Endoscopic therapy  controls pain in some patients who have a prominent stricture in the proximal pancreatic duct.  dilation is followed by ……………stent placement across the stricture.  Pain improves in ………….55 to 100% of selected patients with an isolated proximal stricture during 2 to 69 months of follow-up.  Surgery…………….  If all measures fail to relieve pain, which is superior to endoscopic drainage
  193. 193. Pharmacological#1 197 Treatment- Pain control  Cause …………Pancreatic ductal hypertension secondary to pancreatic outflow obstruction  Medications:  Acetaminophen or NSAIDs  Opiate analgesics  Meperidine 50-100 mg Q3to 4 hrs IV… max dose 600mg/day  Hydrocodone, 10 mg every 6 hours as needed
  194. 194. Pharmacological#2 198  Meperidine ……….. Pethidine  Favored over morphine  Human studies showed that morphine caused …….an increase in sphincter of Oddi pressure.  Despite these data there is no ………..clinical evidence to suggest that morphine can aggravate or cause pancreatitis or cholecystitis.  Problem with Meperidine  normeperidine accumulation after repeated doses of meperidine……………. in renal failure  seizures - neuromuscular irritation
  195. 195. Pharmacological#3 199 Pain Control - Fentanyl IV  An alternative agent ………..if large doses of meperidine needed  ADR…………..Respiratory function depression  Drug Interaction………..  Concurrent use of a calcium channel blocker and a beta-adrenergic blocker with fentanyl has resulted in severe hypotension.
  196. 196. Pharmacological#4 200 Treatment Hyperlipidemia  high TG >500 mg/dl should be treated……………..  Fibric acid derivatives, ……Gemfibrozil, fenofibrate  Niacin, and omega-3 fatty acids.  High doses of a strong statin ……………  simvastatin, atorvastatin, rosuvastatin also…….lower triglycerides, by as much as approximately 50%.  e.g., atorvastatin starting at 10 to 20 mg/day
  197. 197. Pharmacological#5 201 The somatostatin analogue …octreotide  Mechansim………….  inhibits pancreatic secretion and has visceral analgesic effects.  Octreotide may also ………..  have a role in the management of refractory pancreatic fistulas or pseudocysts.
  198. 198. Pharmacological#6 202 Oral pancreatic enzymes  Pancreatic steatorrhea …….stool becomes smelly  A reduction in dietary fat  Pancreatic Enzyme  25,000 to 30,000 units of lipase per meal  H2-receptor antagonists or proton pump inhibitors  Increase effectiveness of enzyme therapy for malabsorption and steatorrhea  Also for stress ulcer
  199. 199. 203
  200. 200. Pharmacological#7 204 Treatment autoimmune chronic pancreatitis  Steroids……dramatic response within 4 weeks.  Prednisolone is initiated at …………  30 to 40 mg/day for 1 to 2 months and  tapered by 5 mg every 2 to 4 weeks.  Maintenance dose…………..  5-10 mg/day of prednisolone needed to prevent relapse.
  201. 201. Complication: Infection 205  Acute necrotizing pancreatitis…….  leading cause of morbidity and mortality  Incidence……… 30%  Patients who develop infection tend to have more extensive necrosis compared to those in whom the necrotic tissue remains sterile.  Occurs late……..  in the course of necrotizing pancreatitis
  202. 202. Complications: Infection 206  Many areas for concern…………..  abscess, pancreatic necrosis, infected pseudocyst, cholangitis,  SEPSIS may occur  Use of broad-spectrum antimicrobials  Multiple organisms…..bowel flora  Prophylactic antibiotics………is NOT recommended  Necrotizing pancreatitis  Significantly increases morbidity & mortality  Usually found on CT with IV contrast
  203. 203. Pancreatitis: Infection 207  Organisms…………..gut-derived  Escherichia coli, Pseudomonas, Klebsiella, and Enterococcus spp.  Initiate with in 48 hrs and continue for 2 to 3 wks.. Imipenim –cilastatin 500mg TID  FQ + metronidazole … 2nd line  Fungal infection /Gram positive……. Uncommon  prophylactic antibiotic use for more than 10 to 14 days…….Is not recommended.
  204. 204. Complications: Pseudocysts 208  Defined as accumulation of pancreatic fluid in a cavity like structure  Incidence……….25%  More common with alcoholic pancreatitis  Resolves spontaneously in most cases  Persistent pain or continued high amylase levels may be present for 4-6 wks afterward  Cyst may become …….  infected, rupture, hemorrhage or obstruct adjacent structures  Asymptomatic, non-enlarging pseudocysts can be…… watched and followed with imaging  Symptomatic, rapidly enlarging or complicated pseudocysts… need to be decompressed
  205. 205. 209
  206. 206. Complications - Others 210  Pulmonary  Atelectasis, pleural effusion, pneumonia and ARDS can develop in severe cases  The diaphragm gets involved  Other……..Metabolic disturbances  hypocalcemia, hypomagnesemia  GI bleeds…..Stress gastritis  Fistula formation…abnormal protrusion
  207. 207. 211