Download Peptic Ulcer Disease (PUD) Tutoring Session 3/15/2017 Sara

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.
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
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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