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Peptic Ulcer Disease (PUD) Tutoring Session 3/15/2017 [email protected] Peptic Ulcer Disease (PUD): large ulcers (>/= 5mm) and extend deep into the muscularis mucosa Causes: Helicobacter pylori NSAIDs Stress-related mucosal damage Pathophysiology Development of ulcers is determined by the balance between destructive (gastric acid and pepsin) and protective (mucosal defense and repair) factors Destructive factors: o Parietal cells: Contain receptors for histamine, gastrin, and acetylcholine Secrete gastric acid o Pepsinogen, the inactive precursor of pepsin, is secreted by chief cells in the gastric fundus. Pepsin activity is determined by pH – activated by acidic pH, reversibly destroyed at pH 7 Protective factors: o Mucus and bicarbonate secretion, intrinsic epithelial cell defense, and mucosal blood flow protect the mucosa from noxious substances o Viscous in nature, near-neutral pH of the barrier protect the stomach from the acidic contents in the gastric lumen o Mucosal repair is related to epithelial cell restitution, growth, and regeneration o Endogenous prostaglandins prevent deep mucosal injury, not superficial damage to individual cells Clinical Presentation Variable - depending on the severity of epigastric pain and the presence of complications o Duodenal ulcer – pain 1-3 hours after meals, pain usually relieved by food o Gastric ulcer – food usually precipitates or accentuates pain Antacids usually provide immediate relief in most ulcer patients Presence or absence of pain does not define an ulcer, and ulcer healing does not necessarily mean the patient will become asymptomatic o “Silent” ulcers (especially in elderly) may be related to different perceptions of pain or masked by analgesic effect of NSAIDs Diagnosis Diagnosis depends on visualization of ulcer crater by either upper GI radiography or upper endoscopy o Upper endoscopy > radiography b/c provides more accurate diagnosis and permits direct visualization of the ulcer and possible implementation of therapeutic maneuvers, such as injection of epinephrine, or clips to control bleeding DiPiro. 10th ed. Chapter 35 Diagnosing H. pylori Either endoscopic or nonendoscopic tests o Endoscopy is more invasive, expensive, and usually requires a mucosal biopsy o Antibiotics and bismuth salts may decrease the sensitivity of rapid urease test – must be held 4 weeks prior o PPIs should be held 2 weeks prior to endoscopic testing If patients have been taking, should have gastric biopsy performed Nonendoscopic tests: urea breath test, serologic antibody detection tests, and fecal antigen test o Urea breath test is most accurate of the noninvasive tests Confirmation of eradication is indicated post-treatment of active ulcers o Urea breath test and fecal antigen are preferred noninvasive tests to confirm H. pylori eradication o Must be delayed 4 weeks after the completion of therapy Complications of PUD Most commonly occur with long-standing PUD Upper GI bleed o Caused by erosion of an ulcer into an artery o Melena (black, tarry stool) o Vomiting blood Perforation o Ulcer may penetrate into an adjacent structure (pancreas, biliary tract, liver) o Sharp, sudden, severe pain that begins in the epigastrium, but quickly spreads over the entire abdomen Obstruction o Mechanical obstruction caused by scarring, muscular spasm, or edema of the duodenal bulb usually resulting from chronic ulceration 1. H. pylori Pathophysiology of Disease. 7th ed. Chapter 13 Figure 13-18 Prevalence varies by geographic location, socioeconomics, ethnicity, and age o Less common in industrialized countries o More prevalent in lower socioeconomic conditions o More common in elderly o African Americans and Hispanics > Whites; thought to be related to socioeconomic status and living conditions Most individuals infected with H.pylori will remain asymptomatic, but 10-20% will develop PUD in their lifetime Environmental factors, host genetics, and strain virulence play an important role in pathogenesis of PUD Gram-negative, microaerophilic, urease producing bacteria o Primarily transmitted person-to-person, by either gastro-oral or fecal-oral contact Resides between the gastric mucus layer and surface epithelial cells o Flagellum allows movement from the lumen of the stomach to the mucus layer o Produces large amounts of urease, which hydrolyzes urea in the gastric juice and converts it to ammonia and carbon dioxide, which produces a neutral microenvironment surrounding the bacterium, which it to survive within gastric acid o Binds epithelium by adherence pedestals, which prevent the organism from being shed during cell turnover and mucus secretion Acid hyposecretion – can suppress parietal cells and damage parietal cells due to inflammation, thereby causing low acid secretion, increased gastrin production, and increased predisposition to gastric cancer Acid hypersecretion – Can cause increased acid production which thereby increases risk of duodenal ulceration Treatment Goal of therapy is eradication of H. pylori, heal ulcer, and cure disease PPI-Based Triple Therapy – 1st line PPI once or twice daily Clarithromycin 500mg Amoxicillin 1gm BID or BID metronidazole 500mg BID Bismuth-Based Quadruple Therapy – alternate initial therapy PPI or H2RA once or Bismuth subsalicylate Metronidazole 250-500mg QID Tetracycline 500mg QID twice daily 525mg QID Non-Bismuth Quadruple or “Concomitant” Therapy PPI once or twice daily Clarithromycin 250Amoxicillin 1gm BID days 1-10 Metronidazole 250-500mg on days 1-10 500mg BID days 1-10 BID days 1-10 Sequential Therapy PPI once or twice daily Amoxicillin 1gm BID Metronidazole 250-500mg BID Clarithromycin 250-500mg days 1-10 days 1-5 days 6-10 BID days 6-10 Hybrid therapy PPI once or twice daily Amoxicillin 1gm BID Metronidazole 250-500mg BID Clarithromycin 250-500mg days 1-14 days 1-14 days 7-14 BID days 7-14 2nd line (salvage) therapy for persistent infections PPI or H2RA once or Bismuth subsalicylate Metronidazole 250-500mg QID Tetracycline 500mg QID twice daily 525mg QID PPI once or twice daily Amoxicillin 1gm BID Levofloxacin 250mg BID 10-14 days of combination therapy; if treating an active ulcer the anisecretory drug is continued for 2 (PPI) to 4 (H2RA) weeks o Proton-Pump Inhibitors/H-2 Receptor Antagonists PPI/H2RA enhances antibiotic activity and stability by increasing intragastric pH and decreasing intragastric volume, thereby enhancing topical antibiotic concentration Should be taken 30-60 minutes prior to meal Prolonged PPI treatment, >2 weeks after eradication is usually not necessary for ulcer healing Single daily dose of PPI may be less effective than BID dosing PPIs are interchangeable – same efficacy in eradication of H. pylori H2RAs should not be substituted for PPI unless patient cannot tolerate PPI o H2RAs are associated with lower eradication rates Antibiotics No single antibiotic eradicates H. pylori o Need 2 antibiotics The most studied and effective drugs include clarithromycin, amoxicillin, metronidazole, and tetracycline o Due to insufficient data, other drugs from the same class should not be substituted (i.e. doxycycline, azithromycin, erythromycin) Bismuth-containing therapy Bismuth subsalicylate, bismuth subcitrate potassium Possible ulcer healing mechanisms include antibacterial effect, local gastroprotective effect, and stimulation of endogenous prostaglandins o Do not inhibit or neutralize acid Use in caution in older patients and in renal failure o May decrease elimination May cause black color to stool and tongue o Long-term use not recommended due to potential for bismuth toxicity Recommended as an alternative 1st line therapy for patients with penicillin allergy o Typically used after treatment failure with PPI triple therapy o Eradication rates similar o QID dosing poor adherence Bismuth salts have topical antimicrobial effect PPI/H2RA drug speeds ulcer healing and relieves pain from active ulcer Sequential Therapy Antibiotics administered in a sequence rather than together Initially treat with antibiotics that rarely promote resistance (amoxicillin) to reduce bacterial load and kill susceptible bugs then administer different antibiotic to kill remaining/potentially more resistant pathogens o Typically amoxicillin x 5 days followed by clarithromycin/metronidazole x5 days o + PPI Non-bismuth quadruple “hybrid” therapy Combines concomitant and sequential therapies Start with PPI + amoxicillin x7 days then add clarithromycin and metronidazole x 7 days o 7 days of dual therapy, followed by 7 days of quadruple therapy OR could use quadruple therapy for 10 days Treatment Failures Salvage treatment should use antibiotics that were not previously used and not associated with resistance (levofloxacin) o Use a drug with topical effect (i.e. bismuth) o Extend duration of therapy to 14 days 2. NSAID Induced Chronic NSAID use has been linked to upper GI tract injury, PUD, gastritis, and superficial erosion Advanced age is an independent risk factor – incidence of NSAID-induced ulcers increases linearly with age Dependent upon NSAID dose, duration of use, and type of NSAID o NSAID potency, duration of action, and propensity to inhibit COX-1 v. COX-2 are associated with increases risk NSAIDs + other medications may further increase risk o Cardioprotective aspirin/antiplatelets, anticoagulants, SSRIs Pathophysiology Cause gastric mucosal damage by direct or topical irritation of the gastric epithelium and systemic inhibition of endogenous mucosal prostaglandin synthesis Onset of injury is due to acidic properties of NSAID o Enteric-coated tablets, salicylate derivatives, and parenteral or rectal preparations have less topical irritant effects Systemic inhibition of protective prostaglandins limits the ability of the mucosa to defend against injury o COX is the rate-limiting enzyme in the conversion of arachidonic acid to prostaglandins and is inhibited by NSAIDs o COX-1 produces protective prostaglandins that regulates GI mucosal integrity, platelet homeostasis, and renal function o COX-2 is induced by inflammatory processes such as cytokines, and produces prostaglandins associated with inflammation, fever, and pain Treatment Antiulcer medications: Relieve symptoms, accelerate ulcer healing, reduce the risk of ulcer recurrence; do not cure disease Histamine-2 receptor antagonists (H2RAs) Proton-pump inhibitors Sucralfate o All patients with PUD will receive antiulcer medication PUD will recur unless the underlying cause is removed NSAID Induced Ulcers: D/c NSAID, change to COX-2 selective NSAID or acetaminophen 4-week regimen of H2RA, PPI, or sucralfate o PPIs usually preferred because they provide rapid symptom relief and ulcer healing o PPI treatment should be extended to 8-12 weeks if NSAID must be continued o Misoprostol co-therapy may be used in high-risk patients Synthetic PGE1 analogue, moderately inhibits acid secretion and enhances mucosal defense 200 mcg PO QID 200 mcg PO TID may be used if patients cannot tolerate higher dose Diarrhea and abdominal cramping limit use in many patients Contraindicated in pregnancy due to production of uterine contractions that may induce labor Proton Pump Inhibitors Omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole Block gastric acid secretion by inhibiting gastric H/K-adenosine triphosphate (ATPase) in gastric parietal cells Only work on those proton pumps that are actively secreting acid – why patients take before eating Delayed-release enteric-coated with pH-sensitive granules: omeprazole, esomeprazole, lansoprazole, dexlansoprazole o pH sensitive granules that prevents degradation and premature protonation of the drug in the stomach, which allows the drug to be dissolved, then absorbed in the duodenum Rapidly disintegrating tablets: lansoprazole Delayed-release enteric-coated tablets: rabeprazole, pantoprazole, OTC omeprazole Similar rates of ulcer healing, maintenance of ulcer healing, and symptom relief Drug Initial Dose Typical daily dose Omeprazole 40mg daily 20-40mg/day Lansoprazole 30mg daily 15-30mg daily Rabeprazole 20mg daily 20-40mg daily Pantoprazole 40mg daily 40-80mg daily Esomeprazole 40mg daily 20-40mg daily Dexlansoprazole 30-60mg daily 30-60mg daily Dose reductions should be considered in patients with severe hepatic disease ADRs: o Short-term: headache, nausea, abdominal pain Long-term: electrolyte abnormalities – hypomagnesemia, vitamin B12 def, iron deficiency, hypocalcemia Increased risk of infection Drug interactions: o Increase intragastric pH – may alter bioavailability of drugs that require acidic environment for absorption o Omeprazole and esomeprazole inhibit 2C19 May decrease elimination of phenytoin, warfarin, diazepam, and carbamazepine May decrease effectiveness of clopidogrel (prodrug, requires 2C19 for activation) o Histamine-2 Receptor Antagonists Cimetidine, famotidine, nizatidine, ranitidine Reversibly compete with histamine for binding to H2 receptors on the basolateral membrane of parietal cells Ulcer healing ~equal among H2RAs with either multiple daily doses or single full dose Tolerance (tachyphylaxis) may occur o Can develop within 3 days of starting treatment and may be resistant to increased doses of the medication Drug Initial Dose Usual Dose Cimetidine 300mg QID, 400mg BID, or 800mg 800-1600mg/day in divided doses QHS Famotidine 20mg BID or 40mg QHS 20-40mg daily Nizatidine 150mg BID or 300mg QHS 150-300mg daily Ranitidine 150mg BID or 300mg QHS 150-300mg daily Renally eliminated – dose adjust in patients with moderate-to-severe renal failure Similar to PPIs, decrease acidity and may alter bioavailability of orally administered drugs Cimetidine = drug interactions, CYP450 o Less potential for CYP450 drug interactions with ranitidine o Famotidine and nizatidine do not interact with CYP450