Lecture Outline
1. Epidemiology
2. Gastric Physiology
3. Pathogenesis of PUD
4. Clinical Presentation
5. Diagnostic Tests and Procedures
6. Treatment
7. Cases
1. Epidemiology
2. Gastric Physiology
AN ULCER RESULTS FROM A MISMATCH BETWEEN AGGRESSIVE AND DEFENSIVE FACTORS.
3. Pathogenesis
a) Role of H. pylori
* Spiral-shaped, flagellated gram-negative organism found primarily in the gastric antrum
* Humans are the major reservoir, 60% of the world is colonized
* No predominant mode of acquisition identified
* Acquisition of H.pylori increases with age and lower socio-economic status
* The orgranism is able to burrow through the gastric mucous layer that overlies the gastric epithelium
* It then attaches itself to the epithelial cell
* It then starts to produce ammonia and bicarbonate from gastric urea, the ammonia and bicarbonate provide the organisms protection form the gastric acid
* Found in about 90-95% of patients with duodenal ulcer and 75-80% of patients with gastric ulcer
* Eradication of H.pylori has shown to dramatically decrease the relapse rate of PUD
* It can cause damage by:
b) Role of NSAIDS
* NSAIDS are generally believed to cause PUD by two mechanisms
* Local irritation which disrupts the gastric mucosa
* Systemic effects on prostaglandin synthesis resulting in decreased PGE2
* Cellular and immune/inflammatory reactions may play a role
* However, only a small percentage of patients develop clinically significant ulcers from NSAIDS
* However, when the number of patients taking NSAIDS in the US is taken into account, we can see that NSAID related gastropathy is a significant issue in healthcare today
c) Role of Corticosteroids
* Controversial
* Earlier studies found an increased risk of ulceration
* More recent studies find that the risk is primarily in patients who are taking NSAIDS as well
* See a 4 fold increase in risk for these people
d) Cigarettes
* Cigarette smoking impairs ulcer healing and promotes recurrence
* Thought to stimulate gastric acid secretion
* May alter blood flow or gastric motility
* May cause bile reflux or reduce production of prostaglandins
e) Alcohol
* Acute ingestion may cause gastritis, gastric mucosal damage, and GI bleeding, however not considered a risk factor for PUD
4. Clinical Presentation
a) Symptoms
* Common signs and symptoms include nausea, vomiting, belching, bloating, heartburn, and epigastric pain
* If these symptoms are present in the absence of ulcer, the term is "non-ulcer dyspepsia"
* Impossible to differentiate between non-ulcer dyspepsia and PUD based on symptoms
* Patients will less often present with complications such as bleeding, obstruction, or perforation without dyspeptic symptoms
* Epigastric pain is the classic and most frequent symptoms of duodenal and gastric ulcer
* Duodenal ulcer-related pain usually occurs 1-3 hours after a meal and is relieved by food
* Gastric ulcer is usually exacerbated by food
* Antacids will usually provide immediate relief
* Severity of symptoms may vary from patient to patient
* Symptoms may also wax and wane with symptom free periods or remission lasting from weeks to years
* Pain does not always correlate with the presence or absence ulcers or erosions
* People with NSAID-related ulceration may be symptom free
* Patients may have melena, orthostatic hypotension, weakness, and anemia if the ulcer is actively or chronically bleeding - refer these patients for immediate medical care
b) Physical Exam
* Epigastric tenderness may occur
* Pain is not a sensitive or specific finding
5. Diagnostic Test and Procedures
a) Routine
* Routine lab tests are not useful in establishing the diagnosis of uncomplicated PUD
* Hct, HgB, and stool hemoccult are useful to detect bleeding
b) H.pylori test
Histology
Culture
Biopsy/gram stain
Biopsy/urease
Urea breath test
Serology
c) Endoscoscopy
6. Clinical Course and Prognosis
7. Treatment
H2-receptor antagonists (H2-RA's)
Mechanism
Efficacy/Therapeutic Use
| Ulcer Type | Duration of Therapy | Cure Rate |
|---|---|---|
| Duodenal ulcer | 4 weeks | 70-80% |
| Duodenal ulcer | 8 weeks | 95% |
| Gastric ulcer | 8 weeks | 80% |
| Gastric ulcer | 12 weeks | 90% |
Adverse Effects
Drug Interactions
Proton-pump inhibitors (PPI's)
Mechanism
Adverse Effects
Drug Interactions
Sucralfate
Mechanism
Dose/Duration
Adverse Effects
Drug Interactions
Misoprostil
Mechanism
Use/Dose/Duration
Adverse Effects
Goals of Therapy
* To cure infection
* Improve symptoms/quality of life
* Prevent disease complications
* To use cost-effective therapy
Specific Agents
1) Bismuth Preparations
* Most commonly used is bismuth subsalicylate (BSS) and colloidal bismuth subcitrate
* Also, recently marketed ranitidine bismuth citrate (RBC)
* At pH of <3.5, BSS turns into salicylic acid and bismuth oxide
* May have protective effects as well as anti-H.pylori effects
* Available as 262 mg caplets and tablets and 262 mg mg/tbsp
* Usual dose is 2 tab qid
* Dose is 1 tab (400 mg) bid
* Please note that bismuth may turn stools and tongue black
2) Amoxicillin
* Aminospenicillin with activity against H.pylori, do not substitute with ampicillin
* Resistance is rare, however, monotherapy is not recommended
* Most common side effects are diarrhea and allergy
* Ususal dose is 2 g per day, divided either qid, tid, or bid
3) Metronidazole
* H.pylori is highly sensitive to this agent
* However, when organism is resistant to metronidazole, success rate drops by 20-40% in metronidazole containing regimens
* Should not be used as monotherapy as resistance may develop
* GI side effects, particularly diarrhea, are common
* May cause a metallic taste in mouth
* Disulfiram reactions can occur; avoid alcohol and alcohol containing products (including certain medication - elixirs)
* Dose: 250 qid, 500 bid, 500 tid ( depends on regimen)
4) Tetracycline
* Good activity against H.pylori, do not substitute with doxycycline
* Resistance is rare
* Avoid use in pregnancy
* May cause photosensitivity
* Take with water to avoid esophageal irritation
5) Clarithromycin
* Good activity against H.pylori
* Resistance may develop
* This agent can replace metronidazole in any regimen
* May cause GI effects (nausea, cramping, diarrhea)
* May lead to drug interactions (especially with cisapride, theophylline)
* Dose is usually 500 mg bid to tid
6) Anti-secretory Agents
a) Proton pump inhibitors
b) H2-RA's
* Please note that the American College of Gastroenterology recommends at least 12 antibiotics in each regimen
* Note that there are two FDA-approved regimens with only one antibiotic, the ACG recommends adding either amoxicillin or tetracycline to these regimens to improve success rates
* Compliance with regimen important for success, trade off between number of pills and frequency of dosing against what patient is willing to take:
*Omeprazole 20 mg bid + Clarithromycin 500 mg bid + Amoxicillin 1 g bid x 10 days
Drug Interactions
* Cimetidine has the greatest potential for drug interactions, ranitidine has a very mild potential
* NSAID's may cause direct damage to the gastric mucosa
* They may also weaken mucosal defenses as an extension of their pharmacological effects (i.e., ketorolac iv and NSAID suppositories causing upper GI bleeding)
* NSAID's inhibit an enzyme called cyclooxygenase (COX), and important enzyme along the arachdonic acid cascade involved in pain and inflammation
* There are two forms of COX, COX-1 and COX-2
* It is believed that COX-2 activity is related to inflammation
* It is believed that COX-1 activity produces potentially protective mediators such as PGE2
* NSAID's differ in their ability to cause gastric bleeding and some of this difference is accounted for by differences is COX-2:COX-1 activity
* Currently, researchers are trying to develop NSAID's with increased COX-2
Risk Factors for NSAID-induced PUD
* Age
* History of PUD
* Dose of Agent
* Concomitant Corticosteroid use
* ? H.pylori
Prophylaxis
"An ounce of prevention is worth a pound of cure"
Misoprostil
* At does of 200 mcg qid, found to decrease the incidence of gastric and dunodenal
* May be more effective at preventing gastric ulcers versus duodenal ulcers
* More importantly, found to decrease the development of serious complications by about 40%
* Use often limited by gastrointestinal side effects
Omeprazole
* At dose of 20 mg qd shown to prevent ulcers (on endoscopy) from NSAIDs
* May be more effective than misoprostil for prevention, need more studies
* No data regarding prevention of complications
* Note that there are two FDA-approved regimens with only one antibiotic, the ACG recommends adding either amoxicillin or tetracycline to these regimens to improve success rates
* Compliance with regimen important for success, trade off between number of pills and frequency of dosing against what patient is willing to take
H2-RA's
* Controversial, previous studies found mostly no benefit from H2-RA prophylaxis
* More recently, famotidine 40 mg bid found decrease the development of ulcers from NSAIDs (on endoscopy)
* Recent trial found omeprazole more effective at preventing NSAID-induced ulcer than ranitidine 150 mg bid
Conclusion: either misoprostil or omeprazole may be used to prevent NSAID-induced ulcers, however, identifying which patients will benefit remains a challenge. If neither of these agents can be used, high dose H2-RA's maybe used.
Treatment of NSAID-induced ulcer
* Once an ulcer has developed, discontinue the NSAID and treat with H2-RA, omeprazole or misoprostil
* However, if the patient requires continued NSAID therapy:
* Either misoprostil 200 ug qid with food or omeprazole 20 mg qd while on NSAID high dose H2-RA's if unable to tolerate or take one of the above medications
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