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Upper GI Disorders
Peptic Ulcer Disease
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PUD Extremely common disorder
4 million people, 350,000 new cases/year>100,000 hospitalizations/year and 3000
deaths/year Ulcer
Disruption in bowel wall extending deep to the muscular mucosa
Resulting from imbalance of mucosal injury, protection and repair
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The protective factors are balanced with the presence of aggressive factors.
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Helicobacter pylori.-colonizes the gastric mucosa (normally a harsh environment for bacteria)-adapted itself to establish colonization
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Adaptive mechanisms: Uses flagella to hide in mucous layer away from
acid Produces urease – hydrolyzes urea into CO2 &
ammonia (creates an alkaline microenvironment) Produces mucinase – thins viscous mucous &
allows bacteria to burrow into mucous layer Provides a passageway for hydrogen ions to enter
epithelium. Not all people infected with H pylori develop
ulcers. The only relatively absolute requirements are:1) Secretions of acid & pepsin, 2) H. pylori infxn 3) NSAID use
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Definitions Peptic Ulcer Disease: A group of
disorders characterized by erosion of the mucosa anywhere in the GI tract that is exposed to the erosive action of acid and pepsin
Erosions (more superficial) may be reepithelialized rapidly by a process called restitution.
Ulcers extend into the deeper layers of the mucosa and require a more complex healing process.
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Definitions Duodenal
Associated with acid outputusually seen in the proximal duodenum [the
1st few cm past pyloric sphincter] Increased pepsinogen I (parietal cell mass)
Gastric ( in Stomach)Usually not associated with acid outputoccur mainly in the antrum of the stomach
Etiology and Pathophysiology
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Types of PUD1-Non ulcer dyspepsia Dyspepsia: an imprecise symptom
complex that includes: epigastric pain or discomfort, Nausea, belching, bloating.
There is over lap between the symptoms reposted by patients diagnosed with peptic ulcer and dyspepsia
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2-NSAID-Induced Ulcers Symptomatic ulcers occur in only 1% of
patients after 3-6 months of NSAIDs This type of ulcer does not correlate with
pain because analgesic action may mask ulcer pain
Mechanisms of Injury: Produce gastric damage by two
mechanismsDirect irritant effectSystemic effect →inhibition of
cyclooxygenase COX-1 → ↓ PG synthesis
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PG protect the GI mucosa by maintaining blood flow & stimulating bicarbonate & mucus
Low PG impair the ability of the gastric mucosa to withstand aggressive factors
COX –2 inhibitions is responsible for anti-inflammatory and analgesic effects
Ulcers occur more frequently in the stomach than in the duodenum.
Many are painless acute, low-dose NSAID-induced lesions
usually heal spontaneously
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Risk factors Age > 60 yrs, High-NSAID dose OR Use of multiple NSAIDs, Hx of ulcer/complication, Co-morbid illness, Concurrent steroid use, GI sx in past 6 mos requiring discontinuation
of the NSAID or the addition of another drug. Patients taking anticoagulants High surgical risk or Debilitated patients
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Association of steroids and PUD is controversial. Steroids may induce ulcers:↑ gastric acid
secretion, ↓ PG production May delay or inhibit healing of ulcers caused by
NSAIDs. Patients taking steroids considered at high risk Recent studies: elderly taking both steroids and
NSAIDs are at much higher risk of PUD than those receiving either agent alone (related to dose & duration of therapy)
3-Adrenocorticosteroids
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Increased basal & postprandial acid secretion Mechanisms:
Enhanced sensitivity of the parietal cell to vagal stimulation,
Impaired acid inhibitory mechanismsZollinger-Ellison Syndrome: caused by a
gastrin-secreting tumor of the duodenum or pancreas → marked gastric acid hypersecretion & recurrent peptic ulceration.
2/3 of tumors are malignant. Found in ~ 0.1% of patients with duodenal
ulcers.
4-Disorders of Acid Hypersecretion
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Risk Factors for PUD
Cigarette smoking Genetic factors Psychological & physiological stress -
multiple trauma, sepsis, neurosurgical problems, ICU stresses
Dietary factors
Clinical Presentation
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Chief complaint:Pain (25% are painless) doesn’t always correlate
w/presence of acid or ulcer cratersDuodenal Ulcer Gastric Ulcer
Most common symptom Most common symptom
Sharp, burning, or gnawing Less typical & predictable
Occurs 1-3 hrs after meals May occur during a mealRelieved by alkali & food Food offers little/no
relief; may precipitate itUsually located in RUQ May extend over a
wide area of epigastrumNocturnal; awakens patient (1-2am)
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Clinical presentation of ZE Syndrome
Similar to sever PUD More persistent Less responsive to standard therapy Abdominal pain; most common Sx Diarrhea: because gastrin inhibits
sodium and water reabsorption from intestine
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Complications
Three Major Complications Hemorrhage Perforation Gastric outlet obstruction
Initially treated conservativelyMay require surgery at any time
during course of therapy
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Hemorrhage
Most common complication of peptic ulcer disease
Develops from erosion of Granulation tissue found at base of
ulcer during healing Ulcer through a major blood vessel
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Perforation Most lethal complication of peptic ulcer Commonly seen in large penetrating
duodenal ulcers that have not healed and are healed and are
located on posterior mucosal wall Occurs when ulcer penetrates serosal
surface Size of perforation directly proportional
to length of time patient has had ulcer
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Gastric Outlet Obstruction Active ulcer formation is associated with edema,
inflammation Duodenum can predispose to gastric outlet
obstruction ↑ contractile force needed to empty stomach
results in hypertrophic stomach wall Obstruction is not totally due to fibrous scar tissue Short duration or absence of pain indicative of a
malignant obstruction Vomiting and Constipation are a common complaint
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Diagnosis
Visualization of the ulcer defines the disease 1-Barium Upper GI Study (X-rays)Can show obstruction, perforation, or penetrationCannot show bleeding 30-60% of ulcers can be detected
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2-Endoscopy Most often used Superior test for diagnosis More costly & less patient acceptance
Can visualize the ulcer Can visualize any bleeding Can treat bleeding Determines degree of ulcer healing
after treatment Tissue specimens can be obtained to
identify and to rule out gastric cancer
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Indications for Endoscopy: New onset dyspepsia in pts > 45 yrs old
(to rule out gastric cancer) Patients with “alarm” symptoms:
Evidence of GI bleeding, anemia, unexplained weight loss, recurrent
vomiting, decreased appetite, easy fullness, dysphagia, abdominal mass,
lymphadenopathy Patients whose symptoms have failed to
respond to initial therapy Patients with recurrent or difficult to
control disease
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Laboratory tests Guaiac test on stool sample CBC should be done if the patient’s
stool is guaiac positive Acute blood loss:
Red cell indices: RBC, Hct, Hgb, Normocytic (MCV), Normochromic (MCH)
Chronic blood loss: Iron deficiency: RBC, Hct, Hgb, MCV,
MCH
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Tests for GUT Blood Very important tool for
screening in the clinic setting
Hemoccult (stool) Gastroccult (stomach) Both are based on the
catalytic activity of hemoglobin during the conversion of guiac into a blue pigment in the presence of peroxide
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Diagnosis of ZE syndrome
Measurement of gastric acid secretion >15 mmol/hr in patients with no prior
gastric surgery > 5 mmol/hr in patients with prior
gastric surgery fasting gastrin level > 1000 pg/ml secretin provocative test: secretion will cause a marked increase
in serum gastrin
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H. pylori TestingIndications for H. pylori testing: New onset dyspepsia in patients < 45
years old (with no alarm symptoms) Active peptic ulcer disease PMH of documented peptic ulcer, which
has not been tested for H. pylori Gastric lymphoma
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Methods of diagnosis for Helicobacter pylori
Test Relative cost
Advantages Disadvantages
Histology + + + Permits visualization; most sensitive (2+ specimens)
Requires endoscopy; time-consuming
Culture + + + Allows determination of antimicrobial sensitivity
Requires endoscopy; technically demanding
Requires several days for result
Rapid Urease (CLO-test)
+ Rapid (20 min-2hrs); inexpensive; Simple to perform
Requires endoscopy
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13C Breath Test
+ +
Can be used multiple times; noninvasive; Non radioactive
May not be widely available; requires
expensive equipment (cost ~ $300)
14C Breath Test
+ + Good for follow-up; noninvasive; rapid (60 min), Less expensive than 13C test (cost ~ $50)
Small radiation exposure; not able to repeat test multiple times
Serology
+ Noninvasive; least expensive; rapid; simplest Look for IgG antibodies to H. pylori
Not useful for short-term f/u of antimicrobial therapy, preferred when endoscopy not done Not useful for pts s/p H. pylori Tx
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Stool Antigens
A stool antigen enzyme immunoassay has a sensitivity of about 94% and specificity of about 90%.
It should not be used to test for eradication of H. pylori until 6- 8 weeks after therapy.
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Gold Standard: Gastric biopsy The Rapid UreaseTest is the most popular
and recommended because of its excellent sensitivity & low cost.
The labeled C breath tests utilize H pylori’s ability to hydrolyze urea into ammonia.
Urea labeled with carbon isotope is administered orally
If organism is present, urea is hydrolyzed & pt will exhale labeled Co2 which can be quantified.
14C is radioactive – not recommended for children, pregnant women, or for multiple uses in the same person. 13C is non-radioactive
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The Serological Test An excellent initial screen to determine
infection because the result is known in 20 min.
H. pylori infection elicits an immune response with an increase in IgG and IgA antibodies. There are commercially available tests that measure IgG antibody.
All of the tests – with the exception of serological testing – may be falsely negative in pts who have taken antibiotics, bismuth compounds, or omeprazole in the recent past.
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TherapyTherapeutic Objectives Relieve pain; control symptoms Prevent pain recurrence Prevent further irritation while healing occurs Remove or treat cause if possible Promote healing Prevent complications Maintain the healed ulcer condition
Indices of Therapeutic Effect:A.Pain relief/Absence of painB.Frequency of antacid useC. Endoscopy (to confirm healing – if symptom
response is inadequate
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General Treatment Principles: Establish diagnosis with certainty (poor
symptom correlation) Utilize non-drug modalities, removing potential
exacerbating factor
Non-drug Therapy: Avoid alcohol Stop smoking Avoid caffeine Avoid aggravating foods Reduce stress Eliminate drug- induced causes (NSAIDs, ASA)
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Action of Anti-Ulcer drug groups
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H2-blockers MOASelectively and competitively Inhibit the action of histamine on H2 receptors of the parietal cells → reducing basal and stimulated secretion of gastric acid
Efficacy Equally Effective for:Treatment of acute ulcers in the absence of H. pyloriTreatment of NSAID-induced ulcersMaintenance therapy in patients unable to tolerate a course of antimicrobial therapy to eradicate H. pylori
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1-H2-blockers
Efficacy70-95% heal rate in 4-8 weeksStandard doses inhibit 50- 80% of 24-hour acid secretionEqual in efficacy to antacid, and sucralfate therapy Effective as single therapy in pts with no H pylori infection
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Side effectsSafe, Frequency of SE is lowCommon SE:
Diarrhea, constipation, Mental confusion, headache, dizziness, drowsiness, and rashes
Confusion/agitation occurs more frequently in elderly, renal & hepatic dysfxn
Similar profile (reported more frequently with cimetidine)Mental status changes, diarrhea, headache (2-3%)Rare: bone marrow suppression (thrombocytopenia, agranulocytosis)
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Cimetidine: Prolonged use – gynecomastia, erectile dysfxn, sperm ct (anti-androgen)
Ranitidine: Hepatitis Famotidine:CNS, headache Nizatidine: Sweating, itching, hepatic
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Table 27-4Cimetidine inhibits oxidative metabolism CYP450Magnitude of interaction varies from patient to patientGenerally it will reduce clearance of another drug by 20-30%Clinically significant in drugs with narrow therapeutic windowAddition of cimetidine may require ↓ dosage of the object drug to avoid increased serum concentrationlidocaine, valium, propranolol, metoprolol, warfarin, phenytoin, theophylline
Drug Interaction Profile
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Other H2-blockers have lower affinity for p450 system; fewer drug interactions:
Cimetidine > ranitidine, nizatidine > famotidine
Cimetidine and ranitidine inhibit renal tubular secretion of procanamide and its metabolite
All 4 drugs can affects absorption and reduce bioavailability of some drugs by requiring gastric PH
Cimetidine ↑ PH →slows dissolution of ketoconazole → ↓ absorption
Cimetidine, ranitidine, nizatidine ↑ absorption of ethanol
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See Table 27-1 and Table 1Control of night time acid secretion is more effective in healing ulcers
May be given as a single bedtime dose for treatment of DU
For ZES: Not totally effective, require large doses and more frequent dosing
The dose to heal an ulcer – DU=GUThe dose to maintain a healed ulcer –DU=GUMaintenance dose is cut in half, single daily dose
Route of Administration and Dosing
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2-SucralfateMOAProtects ulcerated mucosa from aggressive factors
It binds to damaged tissue forming a physical barrier to injury
Efficacy1 gm 4 times daily as effective as 2 gms twice daily
Requires acid medium to work (don’t combine with H2-blocker)
As effective as H2-blockers in promoting DU healing
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Side effectsNot absorbed systemicallyConstipation, xerostomia, skin eruptions, nausea, indigestion, dizziness
Contains aluminum (Al); accumulates in pts with renal dysfxn;
Neuro toxicity; seizures Drug Interaction profileAl dissociates from sucralfate: absorption of TCN, phenytoin, warfarin
Chelation with other drugs given simultaneously
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Dosing: 1 gram, four times daily, before meals & at bedtime (compliance)
For duodenal ulcer, 2 grams bid (before breakfast & at bedtime) may be as effective
Large tablet size – may be difficult to swallow
Route of Administration and Dosing Frequency
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3-Antacids MOARelive pain and promote healing by providing a cytoprotective effect through stimulation of PG
Neutralizing gastric acidStimulating restitution of the gastric mucosa
EfficacyLow to moderate doses may be as effective in healing duodenal ulcers as H2 blockers if taken multiple times a day
neutralize acid; inhibit pepsinogen to pepsin, bile salts
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Antacids High dose as effective as H2-blockers May provide less symptom relief than H2-
blockers High dose: 30 cc po 1hr before & 3 hrs after
each meal & at bedtime (7 doses) May accelerate healing of GU (lack of data to
confirm it, but likely) Currently used for symptomatic relief in addition
to H2-blockers or sucralfate Primarily used on as PRN for pain Liquid formulation are more rapid acting
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Side EffectsAluminum antacids Reacts with intestinal bicarbonatelow alkalosis risk Constipation, hypophosphatemia, renal accumulationMagnesium antacids :Reacts with intestinal bicarbonate - low alkalosis risk, Diarrhea (dose-related), avoid in CRF Combination (Al/Mg) Less ADRs; lower doses usedSodium bicarb: Patients with poor renal fxn –metabolic alkalosis, Sodium overload – 12 Meq/g (edema, CHF, CRF, HTN)
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Calcium antacidsConstipation, rebound hyperacidity (may
not be clinically signif.) More potent & prolonged neutralization,
Systemicalkalinization, milk alkali syndrome, pH ,
Ca++ kidney stonesMalgaldrate: chemical entity composed of aluminum &
magnesium hydroxides (not a physical mixture & lower neutralizing capacity)
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Drug Interaction ProfileChelation – divalent/trivalent cations bind drugs & absorption e.g ciprofloxacin, TCNGastric pH – interfere w/drugs requiring low pH for absorption e.g digoixn, phenytion, isoniazidUrinary pH – may affect drugs requiring acidic/basic urine for elimination
May reduce absorption of tetracyclines, iron, digoxin, & many other drugs
Can reduce absorption of H2-blockers, may effect of sucralfate
Avoid taking other meds 1-2 hrs before & after taking an antacid
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Route of Administration and Dosing frequency
Tablets: chewed/dissolved, palatable. Suspensions work faster; more surface area
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4-Proton Pump Inhibitors: PPI
MOA:Specific inhibitors of gastric acid secretion by irreversible biding to K+-H+ - ATPase ( enzyme which transports acid across parietal cells)
Inhibit basal and stimulated acid secretion
Indicated for short-term treatment of DUIndicated for long-term treatment of ZES
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PPIEfficacyAbsolute healing rates are similarSuperior to H2-blockers with regard to onset of healing & pain relief
Effective in patients refractory to H2-blockers.
may be more efficacious than H2-blockers for the prevention of recurrent GU and DU in patients who must continue on NSAID therapy.
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PPIEfficacyStandard doses inhibit more than 90% of 24-hour acid secretion.
For DU: Omeprazole 20 mg qd 90 –100% healing in 4 weeks
Lansoprazole 30 mg qd 90 – 100% healing in 4 wks
For GU: As effective as H2-blockers for healing ulcer
Higher doses may provide faster relieof pain, recurrence
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For ZES: Long-term efficacy has been observed Decreases diarrhea, heals ulcers Daily dose of 120 mg (mean daily dose 60-
70mg) controls symptoms in > 90% of ptsSide Effects May cause headache, diarrhea, abdominal
pain, nausea, dizziness. Concern over long-term use & development of
carcinoid tumors Treatment: acid will pH; which gastrin
secretion – possible ECL cell hyperplasia (recommended to check serum
gastrin levels annually in pts on long-term therapy)
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PPI : Drug Interaction ProfileAll agents are extensively metabolized by
cytochrome p450 Omeprazole: Inhibitor of oxidative metabolism by p450
systemMay diazepam, phenytoin, warfarin, etc. Omeprazole and Clarithromycin →
concentration of both drugsLansoprazoleMetabolized through p450 system: may
clearance of theophylline (10%)Sucralfate Reduces absorption of PPIsDrugs whose absorption may be impaired from reduced acidity: Ketoconazole, iron, ampicillin, etc.
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Route of Administration and Dosing
See table 1 & 2Rabeprazole is available as a 20mg enteric-coated tablet; dosed once daily.
Pantoprazole is dosed 40mg po qdFor ZES: Longer duration of action so require less frequent dosing
Large doses are necessaryStart at 60mg lansoprazole or 80mg omeprazole po qd
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5-Prostaglandin E1 Analog
MOAInhibits basal & nocturnal gastric acid secretion;
Enhances mucous & bicarb secretion;Reduces pepsin concentration but does not affect histamine stimulated secretion.
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Prostaglandin E1 AnalogEfficacy For prevention of NSAID-induced gastric
ulcers in patients at high risk. Superior to sucralfate in preventing
NSAID-induced gastric ulcers Superior to H2-blockers in reducing
mucosal injury, but may relieve pain less rapidly (H2-blockers more effective for inhibiting gastric acid output, especially at night)
May be effective in healing H2 blocker-resistant ulcers
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Side Effects: Diarrhea, abdominal pain, nausea,
headache, flatulence, constipation Can GFR and improve renal function Contraindicated in women of childbearing
age unless effective contraceptive measures are used (may cause uterine contractions; abortifacient).
Take with or after meals and at bedtime to reduce ADRs
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Drug Interaction Profile No effect on cytochrome p450 system Use of Mg-containing antacids can worsen
misoprostol-induced diarrhea (use an Al-antacid)
Dosing: 200 g qid If patient unable to tolerate: can be given
100 g qid OR 200 g bid or tid (also a small in effectiveness at lower doses)
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6-Bismuth SubsalicylateMOA Direct mucosal protective effect; anti-infective
actions, weak antacid properties It complexes deposit on the surface of H. pylori,
diminishing its ability to adhere to the gastric epithelium. The end result is lysis of the organism within 30-90 min.
The addition of an antimicrobial agent produces a synergistic effect.
May also stimulate production of prostaglandins & modulate the immune response.
Side Effects Abdominal pain, constipation, headache,
confusion, anxiety, tinnitus, tremor.
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Drug Interaction Profile Anticoagulants (plt fxn), May potentiate hypoglycemic effects of
diabetic agents May displace other drugs from protein binding
sites May form complexes with other drugs (TCN,
quinolones) May effects of uricosuric agents, use with omeprazole may systemic absorption
of bismuth (unknown significance)
Dosing 2 tablets QID (1 tablet = 262mg bismuth
subsalicylate; equiv to 100mg salicylate)
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7-Prokinetic Agents: Metoclopramide
MOA Increases GI motility and peristalsis Increases LES tone Antagonizes dopamine receptors.Side Effects Extrapyramidal symptomsDrug Interaction Profile Increased sedative effect of benzodiazepines or
alcohol.Dosing Metaclopramide 5-15 mg dose, up to 4 times a
day (take 30 min before meals). Single dose of 20 mg may be needed in a
provoking situation
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Treatment of NSAID induced ulcer
1-Stop NSAIDs when possible.2- Treat with low dose H-2 antagonist for 8 weeks
Prophylactic therapy In patients unable to discontinue NSAIDs and
have risk factors for development of ulcer1-PPIs: they are preferred if NSAIDs are to be
continued 2-Misoprostol3-H2 antagonist are more effective in healing
duodenal ulcer than gastric ulcer
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Treatment plan & Monitoring1. Assess risk factors for NSAID-induced
ulcers and ulcer-related complications, and when indicated
2.recommend appropriate strategies for reducing ulcer risk (see Table 35-10).
3. Recommend eradication treatment for H. pylori-positive patients taking NSAIDs.
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Treatment plan & Monitoring4. Monitor patients for signs and
symptoms of NSAID-related upper GI complications.
5. Assess and monitor patients for potential drug interactions and adverse effects (especially misoprostol).
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Treatment plan & Monitoring
6. Provide patient education to patients who are at risk of NSAID-induced ulcers or GI-related complications, including
why cotherapy is used with nonselective NSAIDs; when and how to take medications; adverse effects; alarm symptoms; when to contact their healthcare provider; the importance of adherence to drug treatment.
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Eradication of Helicobacter pylori In the past, PUD was considered a chronic
disorder because the ulcer tended to recur. Eradication of H. pylori dramatically reduces ulcer recurrence & cures many patients of their disease.Advantages of eradication:Inflammatory changes return to normalRestoration of microvilli by 4 monthsDecrease in disease recurrenceProblems:Eradication may be difficult; resistance to antibioticsAdverse reactions to antibiotics
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Who should be treated for H. pylori?All pts with established duodenal ulcers with H.
pylori.All pts with gastric ulcers with H. pylori.First or recurrent H. pylori infectionWho should not be treated for H. pyloriAsymptomatic (H. pylori positive or negative)Non-ulcer dyspepsia* (H. pylori positive or negative)Gastric ulcer (H. pylori negative)Duodenal ulcer (H. pylori negative)Gastroesophageal reflux diseaseGallbladder or pancreatic diseaseIrritable bowel or inflammatory bowel disease
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Disadvantages of Maintenance Treatment:
recurrence despite long-term treatment doesn’t change H. pylori colonization long-term drug exposure increased cost potential for disease complications from
recurrence
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H. pylori Eradication Regimens Monotherapy with antibiotics or acid
suppressants have not been optimal Combination of acid suppressants with antibiotics Should contain one anti-secretory agent & at
least 2 antibiotics)
Dosing Clarithro 500 mg bid, Amoxil 1000mg bid,
Metronidazole 500mg bid, Tetracycline 500mg bid
BMT-1: Bismuth 525mg qid + Metronidazole 500mg tid + Tetracycline 500mg qid
BMT-2: Bismuth 525mg qid + Metronidazole 250mg qid + Tetracycline 500mg qid
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Treatment plan & Monitoring1. Assess patient allergies to determine if
allergic to penicillin (or other antibiotics) so that drug regimens that contain penicillin (or other antibiotics) can be avoided.
2. Assess patient use of alcohol or alcohol-containing products with metronidazole and oral birth control medications with antibiotics and counsel appropriately.
3. Assess likelihood of nonadherence to the drug regimen as a cause of treatment failure.
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Treatment plan & Monitoring4. Recommend a different antibiotic
combination if H. pylori eradication fails and a second treatment is planned.
5. Inform the patient of change in stool color when bismuth salicylate.
6. Assess and monitor patients for potential adverse effects, especially those associated with metronidazole, c1arithromycin, and amoxicillin.
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Treatment plan & Monitoring7. Assess and monitor patients for potential
drug interactions, especially those receiving metronidazole, clarithromycin, or cimetidine.
8.Monitor patients for salicylate toxicity, especially patients receiving cotherapy with other salicylates, anticoagulants, and patients with renal failure.
9.Monitor patients for persistent or recurrent symptoms within 14 days after completion of a course of therapy.
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Treatment plan & Monitoring
10. Provide patient education to patients including why antibiotic and antiulcer combinations are
used; when and how to take medications; adverse effects; the importance of adherence to the entire
course of drug treatment; to contact their healthcare provider if alarm
symptoms develop (e.g., blood in the stools, black tarry stools, vomiting, severe abdominal pain), or if symptoms persist or return.
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