Gastro-Esophageal Reflux Disease (GERD) and Peptic Ulcer Disease (PUD) PDF

Faculty of Pharmacy Department of Clinical Pharmacy PHP 543 Gastro-Esophageal Reflux Disease (GERD) & Peptic Ulcer Disease (PUD)  Learning Objectives Identify risk factors associated with GERD & PUD. Describe the clinical presentation of GER...

Faculty of Pharmacy Department of Clinical Pharmacy PHP 543 Gastro-Esophageal Reflux Disease (GERD) & Peptic Ulcer Disease (PUD)  Learning Objectives Identify risk factors associated with GERD & PUD. Describe the clinical presentation of GERD & PUD including typical, atypical and alarm symptoms. Discuss appropriate diagnostic approaches for GERD & PUD. Recommend nonpharmacologic and pharmacologic treatments for GERD & PUD that considers individual patient factors. Modify an unsuccessful treatment strategy for GERD &PUD. Develop monitoring parameters to assess effectiveness and adverse effects of pharmacotherapy for OA  Gastro-Esophageal Reflux Disease (GERD) Definition: “symptoms or complications resulting from the reflux of gastric contents into the esophagus or beyond, into the oral cavity (including larynx) or lung.” It is defined by the presence of: Characteristic mucosal injury seen at endoscopy and/or Abnormal esophageal acid exposure demonstrated on a reflux monitoring study.  Gastroesophageal Reflux Disease (GERD) Types of GERD: a. Nonerosive reflux disease: Symptoms based esophageal syndrome (without erosions on endoscopy ). b. Erosive reflux disease: Tissue injury based esophageal syndrome (with erosions on endoscopy)  Epidemiology One of the most common GI disorders – Up to 20% of Americans have GERD Mortality is rare, but symptoms can significantly decrease quality of life. No gender difference in incidence male = female – Except for its association with pregnancy. – Barrett esophagus and esophageal adenocarcinoma occur more frequently in males  Pathophysiology The retrograde movement of gastric acid or other noxious substances (pepsin, bile acids, pancreatic enzymes) from the stomach into the esophagus is a major factor in the development of GERD. It is commonly associated with defective lower esophageal sphincter (LES) pressure or function  Precipitating Factors Direct irritants to esophageal mucosa: ✔ Citrus fruits, carbonated beverage ✔ Caffeine, (tea, coffee) ✔ Spicy food ✔ Tomato based food (sause, pizza) ✔ Medications: Aspirin, NSAIDs, corticosteroids, bisphosphonates, iron…etc Factors that decrease LES pressure: ✔ smoking, alcohol, chocolate, peppermint ✔ Fried or fatty food ✔ Garlic, onions, chili peppers ✔ Medications: anticholinergics, barbiturates, opioids, estrogen, benzodiazepines, calcium channel blockers…etc. Medications that reduce gastric motility (eg: opiates, tricyclic antidepressants, progesterone, calcium channel blockers)  Precipitating Factors Factors that increase abdominal pressure: ✔ Obesity ✔ Pregnancy ✔ Tight-fitting clothing Recumbency (gravity).  Clinical Presentation Typical symptoms: ✔ Heartburn (pyrosis), ✔ Regurgitation (reflux), ✔ Acidic taste in the mouth Extraesophageal or atypical symptoms: ✔ Chronic cough, asthma-like symptoms, ✔ Recurrent sore throat, laryngitis/hoarseness, ✔ Non-cardiac chest pain or back pain, ✔ sinusitis/pneumonia/ bronchitis/otitis media, dental enamel loss, are less common atypical symptoms ⮚ These symptoms require referral for additional testing.  Clinical Presentation Alarm symptoms: warrant immediate referral for more invasive testing (endoscopy) ✔Dysphagia: difficulty swallowing, caused by obstruction of the esophagus ✔Odynophagia: painful swallowing usually associated dysphagia ✔Hematemesis: vomiting blood (could be red or coffee ground) from bleeding esophageal erosions ✔Unintentional weight loss:  Long-term complications: Esophageal erosion, strictures, or obstruction. Barrett’s esophagus: – Replacement of squamous epithelial cells with columnar epithelial cells within the lower esophagus, resulting in increased risk of esophageal carcinoma) Esophageal cancer Reduction in quality of life.  Diagnosis It is based on: Clinical History & symptom presentation, Endoscopic evaluation of esophageal mucosa Reflux monitoring, Response to therapeutic intervention.  Diagnosis Clinical history: – including presenting symptoms and risk factors. – The most useful tool in the diagnosis of GERD. Patients presenting with uncomplicated, typical symptoms of reflux (heartburn and regurgitation) should start lifestyle modifications plus empiric acid-suppressing therapy (Antacids/H2RAs PRN). – They should not receive invasive esophageal evaluation as a first step.  Diagnosis Endoscopy: – Help assessing mucosal injury and identify complications such as erosions & strictures. – Indicated ONLY in: Patients with alarm symptoms or Patients unresponsive to empiric trial of proton pump inhibitor (PPI). ⮚ A mucosal biopsy is taken to identify Barrett esophagus and adenocarcinoma.  Diagnosis Ambulatory esophageal reflux monitoring: – Ambulatory pH testing. – identifies patients with excessive esophageal acid exposure and frequency of reflux episodes. – Useful in patients for whom the diagnosis of GERD is suspected but not clear, and endoscopy shows no objective evidence of GERD. – It is recommended that reflux monitoring be performed off therapy to establish the diagnosis.  Diagnosis Manometry: Testing to determine esophageal pressure. Recommended for preoperative evaluation, But it has no role in the diagnosis of GERD ☞ Routine screening for H. pylori infection and empiric eradication of H. pylori are not recommended in patients with GERD  Treatment Goals of therapy: – Alleviate symptoms. – Promote healing of mucosal injury. – Prevent recurrence of disease. – prevent complications. – Provide cost-effective therapy. – Improve QOL.  Non-Pharmacologic Therapy: Lifestyle Modifications Stop smoking & alcohol. Lose weight (if overweight) Raise the head of the bed 6-8 inches Avoid late meals or bedtime snacks Avoid lying down immediately after eating (remain upright for at least 2 hrs after meals). Avoid aggravating foods and beverages Avoid tight-fitting clothing (decreases intra-abdominal pressure). Evaluate patient’s medication list Non-pharmacologic interventions and lifestyle modifications ALONE are unlikely to control symptoms in most patients.  Pharmacologic Therapy ✔ Antacids ✔ H2 Receptor Antagonists (H2RA) ✔ Proton Pump Inhibitors (PPI) Combination: H2RA or PPI + antacid The management approach (either step-up or step down) is based on: the frequency and severity of symptoms the presence of erosive esophagitis or Barrett’s esophagus on endoscopy, if previously performed  Antacids calcium carbonate, aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, or any combination. Neutralizing acid and raising intragastric pH results in decreased activation of pepsinogen and increased LES pressure Quick onset: 5-15 minutes Short duration of action: 1-3 hours Useful for daytime symptomatic relief but does not promote healing Good as “add-on” treatment with other acid-suppressing therapies May need higher doses or alternate therapy if symptoms persist for > 2 weeks  Antacid Choices Antacid Comments Calcium Antacid of choice in pregnancy carbonate May cause constipation (Tums, Caltrate) Caution in renal impairment Binds to phosphate ⇒ hypophosphatemia Aluminum May cause constipation hydroxide Accumulation in renal failure (Amphogel, Binds to phosphate ⇒ hypophosphatemia ⇒ anorexia AlternaGEL) and muscle weakness; possibly osteoporosis (if prolonged) Magnesium May cause diarrhea hydroxide Accumulation in renal failure (Milk of Magnesia) Sodium Sodium content ⇒ edema, fluid retention, HTN bicarbonate Contains aspirin (caution warfarin or pregnant pts) (Alka Seltzer) Caution in renal impairment  Antacid Choices Antacid Comments Combination Aluminum- Side effect of either ingredient can occur Mg Diarrhea predominant (Maalox, Mylanta, Riopan) Antacid + Antirefluxant : forms a viscous layer on top of alginic acid gastric contents to act as a barrier to reflux (Gaviscon) (variable added efficacy). Counseling: Tablets must be chewed and followed by full glass of water to be effective Only works in upright position (not for HS use)  Antacids Drug interactions May interfere with absorption of drugs that require acidic environment – Digoxin, phenytoin, isoniazid, ketoconazole, iron Antacids containing Ca, Mg, or Al can cause chelation of iron, levothyroxine, tetracyclines and fluoroquinolones Solution?  H2-Receptor Antagonists (H2RAs) Cmetidine (Tagamet), famotidine (Pepcid), and nizatidine (Axid). Reversibly inhibit H-2 receptors on the parietal cell Small doses can be used for on-demand therapy for intermittent mild-to-moderate GERD. – preventive dosing before meals or exercise is also possible. – Higher doses are often necessary for more severe symptoms or for maintenance dosing. Prolonged use is associated with the development of tolerance and reduced efficacy (tachyphylaxis). H2RAs are less effective than PPIs in healing erosive esophagitis.  H2-Receptor Antagonists (H2RAs) Adverse effects: Most are well tolerated. Central nervous system (CNS) effects such as headache, dizziness, fatigue, somnolence, and confusion are the most common. Elderly and patients with reduced renal function are at higher risk. Prolonged cimetidine use is associated rarely with gynecomastia. Drug interactions: Can affect the absorption of drugs dependent on lower gastric pH (e.g., ketoconazole, itraconazole, iron, atazanavir, delavirdine, indinavir, nelfinavir) or increases in absorption leading to potential toxicity (e.g., raltegravir, saquinavir). Cimetidine also inhibits cytochrome P450 (CYP) enzymes 1A2, 2C9, 2D6, and 3A4. – Warfarin, theophylline, and other agents metabolized by these enzymes can be affected.  Proton Pump Inhibitors (PPI) Irreversibly inhibit the final step in gastric acid secretion⇨ greater degree of acid suppression. More effective and longer duration of action than high dose H2RAs but also more expensive. Effective for erosive and non-erosive esophagitis Has shown to normalize the impaired QOL caused by GERD Equivalent efficacy between products Proton Pump Inhibitors (PPI)  Proton Pump Inhibitors (PPI) Drug interactions interaction with drugs with pH-dependent absorption (e.g., ketoconazole, itraconazole, protease inhibitors) Inhibition of CYP450: – Omeprazole is the strongest CYP2C19 inhibiter – inhibits the metabolism of substrates, such as diazepam, citalopram, warfarin, phenytoin ⇨ toxicity – Potential reduced effectiveness of clopidogrel through inhibition of CYP2C19- mediated conversion to active metabolite by omeprazole. Recommendation from the U.S. Food and Drug Administration (FDA) with clopidogrel, is to avoid omeprazole and to use pantoprazole as an alternative.  Proton Pump Inhibitors (PPI) Adverse Reactions: Generally, well tolerated. Most frequently reported: – GI discomfort Diarrhea or constipation, nausea, abdominal pain – CNS Headache, dizziness Rare/isolated reactions – Pruritus, increased LFTs Rebound acid hyper-secretion – Degree is related to duration of treatment  Proton Pump Inhibitors (PPI) Major Adverse Reactions: (associated with long-term use) Increase risk of fracture (hip, wrist, spine): – Recommendations: limit dose and duration; ensure adequate calcium (Ca citrate) and vitamin D; BMD screening if at risk of low bone mass; weight-bearing exercise Hypomagnesemia: Reevaluate need of PPI use; limit dose and duration; consider baseline testing; (presence of diuretics, digoxin); supplementation Clostridium difficile–associated diarrhea – Reevaluate need of PPI use; limit dose and duration; evaluate for C. difficile if patient receiving PPI has diarrhea that is not improving; have patients report diarrhea Community-acquired pneumonia – Reevaluate need of PPI use; limit dose and duration; assess vaccine status  PATIENT COUNSELING Most effective when taken orally 30–60 minutes before meals – Once daily →take before breakfast. – Twice-daily, the 2nd dose should be taken 30–60 minutes before the evening meal instead of at bedtime All caps/tabs are delayed release (do not crush or chew) If difficulty swallowing: – Open the capsules and sprinkle the content over applesauce, but do not chew mixture – use liquid formulations available Reevaluate need of PPI use; limit dose and duration ensure adequate calcium, magnesium and vitamin D Weight-bearing exercise  Other Agents Prokinetic Agents: Metoclopramide, bethanechol or cisapride – Inferior efficacy and more adverse effect profiles when used for GERD treatment. – Not recommended as monotherapy for treatment of GERD – Might be used only in selected patients as add on therapy – QID dosing, 30-60 minutes before meals & HS – 20-50% experience SE (drowsiness, fatigue, EPS, diarrhea, GI cramp) Baclofen – For refractory GERD pts in the presence of objective evidence of GERD. – No long term data – Limited use due to SE (dizziness, somnolence, constipation) Combination Treatment for GERD PPI + antacid – Zegerid® (omeprazole + Na bicarbonate) PPI + H2 blocker – PPI BID + H2 blocker HS for breakthrough nocturnal acid secretion PPI + prokinetic agent – For severe GERD with evidence of gastroparesis  Therapeutic plan for GERD Initial treatment will depend on the severity, frequency, and duration of symptoms “Step-up” treatment Approach For patients with mild and intermittent symptoms (fewer than two episodes per week) and no evidence of erosive esophagitis: Initially recommend lifestyle and dietary modification + as needed, low-dose H2RAs + concomitant antacids and/or sodium alginate as needed If symptoms continue increase the dose of H2RAs to standard dose, twice daily for a minimum of two weeks. if symptoms of GERD persist, switch to once-daily proton pump inhibitors (PPIs) at a low dose and then increase to standard doses if required for up to 8 weeks Advantages: ✔Avoids overtreatment. ✔ Lower initial drug cost. American College of Gastroenterology (ACG) Treatment Guideline Recommendation : In patients with frequent symptoms (two or more episodes per week), and/or severe symptoms that impair quality of life, but no alarm symptoms: An 8-wk trial of empiric PPIs once daily before a.m meal is recommended. - If adequate response after 8 wks ⇨ Discontinue the PPI. - If NO adequate response OR if symptoms return when PPI is discontinued ⇨ endoscopy is recommended. The addition of bedtime H2RA ( as needed) has been suggested for patients on PPIs with nocturnal (nighttime) symptoms. Twice-daily PPIs is recommended if partial response to once-daily PPIs or persistent nocturnal symptoms. Twice-daily PPI therapy is superior to once-daily double-dose PPI American College of Gastroenterology (ACG) Treatment Guideline Recommendation : On-demand PPI therapy: Consider in patients who continue to have symptoms when PPI therapy is discontinued (WITHOUT erosive or Barrett’s esophagitis). PPIs are taken only when symptoms occur and discontinued when they are relieved. American College of Gastroenterology (ACG) Treatment Guideline Recommendation In patients with Erosive esophagitis: Treatment with standard-dose PPI once daily is recommended PPIs maintenance is recommended (longer than 6 months) Maintenance therapy with PPIs should be administered in the lowest dose that effectively controls GERD symptoms and maintains healing of reflux esophagitis. PPI therapy indefinitely or antireflux surgery for patients with LA grade C or D esophagitis. American College of Gastroenterology (ACG) Treatment Guideline Recommendation Treatment Recommendation refractory GERD: In refractory GERD (persistent heartburn and/or regurgitation despite 8 weeks of double-dose PPI therapy) Optimization of PPI therapy. Esophageal pH monitoring (performed OFF PPIs). Consider antireflux surgery American College of Gastroenterology (ACG) Treatment Guideline Recommendation Treatment Recommendation Pregnancy: life-style modification If fail, antacids (aluminum-, calcium-, or magnesium-containing), alginates, and sucralfate are the first-line therapeutic agents. All H2RA and PPIs are FDA category B, except omeprazole, which is FDA category C. “Step-up” treatment Approach  GERD Treatment Algorithm  Patient Case A 55-year-old man with an 8-month history of GERD symptoms 4–5 days/week has been receiving lansoprazole 15 mg daily by mouth, with the use of magnesium hydroxide for breakthrough symptoms. His symptoms are still present 3–4 days/week and are disruptive to his daily life. He has implemented lifestyle modifications and has been adherent to lansoprazole. His medical history is significant for hypothyroidism. He takes levothyroxine 100 mcg once daily. An endoscopy last week revealed no ulcers or erosions. Which treatment approach is best for this patient? A. Add metoclopramide 10 mg four times daily. B. Increase lansoprazole to 15 mg twice daily. C. Switch to famotidine 20 mg daily. D. Add sucralfate 1000 mg four times daily.  Peptic Ulcer Disease (PUD) Peptic ulcer disease (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. Gastric ulcer Duodenal ulcer PUD is a significant cause of morbidity and is associated with substantial health care costs  Peptic Ulcer Disease (PUD) Most common etiology: (1) H. pylori infection (2) use of nonsteroidal anti-inflammatory drugs (NSAIDs) (3) stress-related mucosal damage (SRMD).  Other Causative Factors Cigarette smoking: – higher prevalence of ulcers in H. pylori-infected patients. Dietary factors: such as coffee, tea, cola, alcohol, and spicy foods - may cause dyspepsia but have not been shown to independently increase PUD risk. psychosocial factors: such as life stress, personality patterns, and depression may influence PUD prevalence.  Epidemiology ❑ 70% of patients with PUD are b/w 25-64 years old ❑ 50-90% of ulcers recur within 1 year of initial healing ❑GU tend to occur much later in life than DU, with the peak incidence of GU occurring in patients over 60 years of age (may be due to higher NSAID use). ❑Peptic ulceration occurs in up to 30% of chronic NSAID (including aspirin) users. ❑The prevalence of H. pylori infection in the United States and Canada is about 30%, whereas the global prevalence is greater than 50%. 51  Complications of PUD ❑ Pts with PUD have a 30% probability of lifetime complications: ✔ Active bleeding: may be occult (hidden) or may present as Melena or Hematemesis. ✔ Perforation ✔ gastric outlet obstruction: Caused by ulcer-related inflammation or scar formation near the peripyloric region. ✔ Complications of untreated or undiagnosed H. pylori infection include PUD and gastric cancer.  Pathophysiology An Imbalance between Factors responsible for Factors responsible for food breakdown mucosal defense and repair Gastric Pepsin acid H2CO3 Mucus PGs Summer 2017 53  Clinical Presentation Dyspepsia – Indigestion, heartburn, postprandial belching, bloating, flatulence, fullness, early satiety, – nausea, anorexia, occasional vomiting Epigastric pain: – Gastric ulcer (GU) Pain occur soon after a meal often made worse by eating. – Duodenal ulcer (DU) Usually 1-3 hrs after a meal, possibly worse at night. may be relieved by eating. 1-2% of pts will have clinically silent ulcers  Clinical Presentation Alarm symptoms – Sign of GI bleeding: anemia, hematemesis, melena (black tarry stool due to upper GI bleeding). – Unintentional weight loss – Palpable mass or lymphadenopathy – Severe spreading upper abdominal pain  Diagnosis Endoscopy: Invasive and expensive, thus should be reserved only for – Pts with alarm symptoms or – older than 55 y/o with new onset dyspepsia  Pts without alarm symptoms or under 55 y/o, should test 1st for H. pylori  Diagnostic tests for H. pylori Urea breath test (UBT):(97% sensitive, 95% specific) first-line test to detect active H. pylori infection Detects the exhalation of radiolabeled CO2 released as a result of H. pylori hydrolysis of the ingested radiolabeled urea. Used to make a diagnosis and to test for eradication. Recent use of antibiotics or PPIs can cause false-negative results. – Discontinue PPI or antibiotics at least 2 - 4 weeks before repeating UBT. Stool antigen tests: (90% sensitive, 87% specific). Polyclonal or monoclonal antibody tests that detect the presence of H. pylori in stool They can be used to make a diagnosis and to confirm eradication. Recent use of antibiotics, PPIs or bismuth can cause false-negative results. – Discontinue antisecretory agents or antibiotics at least 2 - 4 weeks before stool antigen testing.  Diagnostic tests for H. pylori Serologic tests: (85% sensitive, 79% specific). Quick assessment within 15 minutes Limited clinical utility (false +ve) – Detect antibodies to H. pylori in the blood. – Cannot distinguish between active infection and past exposure, because antibodies persist for long periods after eradication. Cannot use to test for eradication after treatment.  Diagnostic tests for H. pylori Invasive (endoscopic) tests Used less frequently than noninvasive tests. Histology: 90%–95% sensitive, 98%–99% specific. – subject to sampling error Rapid urease tests:(80%–95% sensitive, 95%–100% specific). – detect the presence of ammonia (NH3) in a sample generated by H. pylori urease activity – False-negative results can be caused by a partialy treated infection, GI bleeding, achlorhydria, or use of PPIs, H2RAs, or bismuth. Discontinue antisecretory drugs for at least 1 week before the test is performed. Culture:(100% specific). – costly, time-consuming, and technically difficult  Treatment for H. pylori infection Recommend eradication regimens: – “Triple therapy”: first-line PPI + clarithromycin + amoxicillin (or metronidazole in case of penicillin allergy) for 14 days OR – “Quadruple therapy”: alternative first-line (if clarithromycin resistance rates are high (>15%) or patient has prior macrolide exposure) PPI + bismuth subsalicylate + metronidazole + tetracycline (or doxycycline in case of drug shortage) for 14 days Caution: neurotoxicity and salicylate toxicity in renal impairment Alternative Regimens for H. pylori Concomitant Therapy – Could be used in case of treatment failure of the 1st line regimen PPI + clarithromycin + amoxicillin + metronidazole given concomitantly x 10 -14 days Higher eradication rate than standard triple therapy, but more adverse effects. Alternative Regimens for H. pylori Sequential Therapy – PPI + amoxicillin 1g (both BID) x 5 days, then PPI + clarithromycin 500 mg + metronidazole 500 mg (all BID) x 5 days – High efficacy rate in Europe & China but not validated in North America – Complexity of regimen makes it less desirable as first line therapy Alternative Regimens for H. pylori Rescue/Salvage Therapy Levofloxacin-based triple therapy: PPI+ levofloxacin + amoxicillin (or metronidazole) for 14 days – Eradication rates 63-94% – Considered 3rd line due to concerns of resistance and lack of validation in US.  Treatment for H. pylori infection Possible causes for treatment failure: non-adherence, antimicrobial resistance or reinfection,. Factors associated with decreased adherence include: polypharmacy, need for frequent drug administration or long treatment duration, and intolerable side effects. Potential adverse drug effects include: – taste disturbances (clarithromycin and metronidazole), – nausea, vomiting, abdominal pain, and diarrhea. – Superinfections with oral thrush or vaginal candidiasis. Preexisting antimicrobial resistance accounts for up to 70% of all treatment failures and is most often related to metronidazole or clarithromycin.  Important tips in Treatment for H. pylori infection PPI should be used twice daily. PPI for an additional 4 weeks is needed to heal ulcer. Substitution of one PPI for another is acceptable and does not affect eradication rates. The cure rates of H. pylori with H2RAs in combination with antibiotics are lower than with PPIs.  Important tips in Treatment for H. pylori infection PPI should be used twice daily. PPI for an additional 4 weeks is needed to heal ulcer. Substitution of one PPI for another is acceptable and does not affect eradication rates. The cure rates of H. pylori with H2RAs in combination with antibiotics are lower than with PPIs. Monotherapy with a single antibiotic is not recommended due to high failure rates. Different antibiotics should be used if a second course of H. pylori eradication therapy is required. Eradication may be confirmed by either the urea breath test or stool antigen testing. FDA approve combination therapies ❑ All are expensive, but may increase adherence to the regimen. Pylera® ▪ (bismuth subcitrate 140 mg, metronidazole 125 mg, and tetracycline 125 mg) in one cap. ▪ Take 3 capsules QID in combination with omeprazole 20mg BID x 10 days ✔PPI should be added 67 FDA approve combination therapies Helidac ®: ▪ a package of 14 blister cards. ▪ Each card containing a single-day supply. ▪ One dose consists of 2 bismuth salicylate chew tabs (525 mg) + one metronidazole tab (250mg) + one tetracycline caps (500mg) ✔PPI should be added 68  FDA approve combination therapies ▪ PrevPac® ▪ Supplied as daily cards (14 cards each 6 capsules) ▪ ONE dose contain (LANSOPRAZOLE 30mg + amoxicillin 1000mg + clarithromycin 500mg (2 tab.) ▪ Take one dose BID for 14 days 69  NSAID-induced PUD Risk Factors for NSAID-Induced PUD Category Risk Factors Low risk No risk factors Moderate risk Age > 65 yr (1 or 2 risk History of co-morbid GI conditions: PUD, factors) Upper GI bleed, Helicobacter pylori infection Concurrent use of antiplatelet medications: aspirin (including low dose), corticosteroids, or anticoagulants High-dose NSAID therapy (e.g., ibuprofen 2400 mg/day, naproxen 1000 mg/day) High risk > 2 risk factors Primary prevention of NSAID-induced PUD Determine the level of GI-related risk (low, medium, high) – Use gastroprotective agent and/or COX2 inhibitors if there is any risk GI factors. H. pylori infection is thought to confer additive risk of GI toxicity in NSAID users. – Test and treat H. pylori infection if the patient is beginning long-term NSAID therapy. Primary prevention of NSAID-induced PUD ⮚ Use of gastro-protective agents PPI daily. A full-dose H2 blocker daily. The prostaglandin analog misoprostol four times daily (tolerance!!!). –poorly tolerated because of excessive nausea, vomiting, diarrhea, and abdominal cramping. –Contraindicated in pregnancy (category X) »Induces uterine contractions & abortion ⮚PPIs are the preferred gastroprotective agents for both treatment and prevention of aspirin- and NSAID- associated GI injury. Primary prevention of NSAID-induced PUD Take the lowest effective dose of the NSAID, and take only when needed, for the shortest duration. Switch to a COX-2 selective inhibitor (“coxib”). Semi-selective NSAIDs (NSAIDS with some COX2 selectivity) seem to cause less GI SE (Meloxicam, piroxicam, diclofenac, ibuprofen) ✓ Naproxen is considered a moderate GI risk. ✓ Other agents such as indomethacin, and ketorolac are considered high-risk agents.  Treatment & secondary prevention of NSAID-induced PUD – Discontinue or lower NSAID dose, if possible. Ulcers will heal with appropriate treatment, but healing may take longer with continued NSAID use. Consider COX-2 inhibitor as alternative in non-CV patients. – Test for H. pylori and treat, if present. – PPIs Drugs of choice to heal NSAID-induced ulcers Drugs of choice for secondary prevention (when NSAID use must be continued once diagnosed with an NSAID-induced ulcer) Misoprostol appears to be as effective as PPIs for healing and secondary prevention, but poorly tolerated. H2RAs and sucralfate are inferior to misoprostol and PPIs in healing and preventing recurrence. 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. – patients who need to be on long-term NSAIDs or high-dose corticosteroids and are at high risk for bleeding.  Treatment of Refractory Ulcers ❑ Refractory Ulcers are ulcers that persist (fail to heal) despite 8 to 12 weeks of treatment ▪ Requires thorough assessment, including evaluation of medication compliance., and recent OTC/ prescription medication ▪ Tolerance has been reported with as few as 4 weeks of H2RA therapy, ⇨ change to PPI therapy ▪ Ulcer biopsy to exclude malignancy ▪ H. pylori testing (if not done initially), ✔ Increasing dose of PPIs may heal up to 90% of refractory ulcers after 8 weeks 77  Treatment Algorithm for PUD  Stress ulcer in critically ill patients Superficial mucosal damage has been reported to occur during the first 24 hours of hospital admission in 75% to 100% of intensive care unit (ICU) patients. Stress ulcer: Deeper mucosal ulceration; may lead to bleeding and hemodynamic compromise Contributing factors to stress ulcer development – Hypoperfusion of the GI tract due to hypovolemia or hypotension – Increase stress hormones such as cortisol & catecholamine – Loss of defense mechanisms: mucous/bicarbonate layer, prostaglandins,… Mortality from stress‐related bleeding ranges from 50% to 70% in the critically ill. PPIs and H2RAs are the drugs of choice for stress ulcer prophylaxis (SUP). 79  Indications for SUP in ICU Patients Prophylaxis is recommended in patients with ONE of the following: (Major Risk Factor) Mechanical ventilation for 48 hours or longer Coagulopathy: Platelet count < 50,000/mm3 INR > 1.5 or aPTT > 2 times control History of GI ulcer/bleeding within 1 year of ICU admission. Thermal injuries (burn) to more than 35% of body surface area Multiple traumas (injury severity score ≥ 16) Spinal cord injuries Head trauma (or Glasgow Coma Score ≤ 10)  Indications for SUP in ICU Patients Prophylaxis is recommended in patients with two or more of the following (Minor Risk Factor) Sepsis. – Hypotension & hypoperfusion. – Acute organ dysfunction (AKI or liver failure) Major surgery (Extended surgeries times exceeding 4 hrs). High-dose corticosteroids. Concomitant NSAIDs use. Advanced age (70 years or older). ICU>1 week  H2RA vs. PPI H2RA PPI Can be used IV, PO or enterally Can be used IV, PO or enterally Multiple dosing due to the short Despite short elimination half- duration of action lives, PPIs suppress acid secretion for 20 hours or more, permitting once-daily dosing. Development of tolerance & Tachyphylaxis does not occur Tachyphylaxis with PPIs. Require renal dose adjustment No adjustment needed for renal for CrCl