ahmed mayet pharm.d.,bcps associate professor king saud university
TRANSCRIPT
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Ahmed Mayet Pharm.D.,BCPSAssociate ProfessorKing Saud University
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Upper GI Disorders
Peptic ulcer disease includes duodenal ulcer, gastric ulcer, gastritis, duodenitis, Zollinger Elison syndrome
Gastroesophgeal Reflex Disease (GERD)
Stress ulcer
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Peptic Ulcer
Ulcerative disorders of the upper GI tract involving most proximal portion of the duodenum and the stomach
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Peptic Ulcer Disease
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Peptic Ulcer
What is a peptic ulcer? An ulcer is an erosion of the gut wall, formed in the
presence of gastric acid and pepsin, extending to the sub-mucosa or deeper.
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Causes of Ulcer
The inside of the stomach is bathed in about 2 liters of gastric juice every day
Gastric juice is composed of digestive enzymes & concentrated hydrochloric acid, which can readily digest the toughest food or microorganism
The gastroduodenal mucosal integrity is determined by protective (defensive) & damaging
(aggressive) factors
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Causes of Ulcer
The Defensive Forces
Bicarbonate
Mucus layer
Mucosal blood flow
Prostaglandins
Growth factors
The Aggressive ForcesHelicobacter pylori
HCl acid
Pepsins
NSAIDs
Bile acids
Ischemia and hypoxia.
Smoking and alcohol
When the aggressive factors increase or the
defensive factors decrease, mucosal damage
will result, leading to erosions & ulcerations
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Causes of Ulcer
Imbalance between aggressive factors and defensive factors resulting in peptic ulcer
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Aggressive factors vs. defensive factors Aggressive factors
Hydrochloric acid Pepsin NSAIDS H.Pylori
Defensive factors
Mucus Bicarbonate Epithelial cell
junction Blood flow
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Defensive factors mediator Prostaglandins
Mediate production of mucus Mediate secretion of bicarbonate Regulate gastric mucosal blood flow Inhibit acid secretion
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Why do all humans develop peptic ulcer?
The normal capacity of gastric and proximal duodenal mucosa to resist the corrosive effects of acid and pepsin is unique.
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Parietal Cell
Found along the course of mucosal glands of the body and fundus of the stomach, secrete Hydrochloric acid (HCL)
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Pepsin
Pepsinogen produce by chief cell and mucus cell (body) and convert to pepsin by HCL
Pepsin work well if pH is below 2 and inactivated in neutral pH
Pepsin has corrosive effect
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Cigarette smoking
Stimulation of gastric acid secretion and bile salt reflex
Alteration in mucosal blood flow Reduction in prostaglandin synthesis Lower bicarbonate secretion
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NSAIDS
Direct irritation to GI mucosa causing ulcer
Decrease prostaglandin synthesis lead to decrease blood flow, mucus secretion, decrease bicarbonate secretion
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H Pylori
Aggressive factors Major cause of peptic ulcer disease Up to 90% cause of duodenal ulcer Up to 70% cause of gastric ulcer Release toxic substances to cause
ulcer Survive well in gastric mucosa
(antrum)
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H Pylori
Cause inflammatory process in GI mucosa
Decrease mucus viscosity Increase acid permeability Increase serum gastrin level Increase parietal cell mass and acid
secretion
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Prevalence
Duodenal ulcer is more in men than in women
Gastric ulcer is same as in men and women
Gastric ulcer and duodenal ulcer are increase with age.
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Clinical Presentation
Duodenal Ulcer Burning, gnawing, and
aching abdominal pain occur when stomach is empty or just before the meal or at sleep and relieve by food and antacid.
Patients are over weight Patient may or may not
has pain
Gastric ulcer Burning, gnawing, and
aching abdominal pain occur 1 to 3 hours after the meal and relieve by induced vomiting.
Patients are usually thin. Patient may or may not
has pain
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Complication
Bleeding ulcer Perforation of the stomach or
duodenum into peritoneal cavity Pyloric outlet obstruction Penetration of the ulcer into
pancreas
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Diagnosis
Upper GI endoscope examination Barium examination All gastric ulcer patient’s must be
biopsied to rule out gastric ulcer
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Treatment goals
Promote ulcer healing Relieve pain Prevent recurrence Prevent bleeding Prevent perforation Prevent gastric outlet obstruction
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TreatmentGeneral Measures Avoid NSAID Avoid smoking Avoid caffeine - containing
beverages if can not tolerate Avoid spicy food if can not tolerate Eat small meals in DU more
frequently Do not eat large meal in GU
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Drugs Therapy
H2 receptor antagonists Proton pump inhibitors Cytoprotective agents Prostaglandin agonists Antacids Antibiotics for H Pylori eradication
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H2 receptor antagonists
Histamine release from mass cells, bind to H2 receptors and activates adenylate cyclase and increase the levels of Camp and activate the proton pump of the parietal cell hydrogen ions secretion. H2 receptors antagonists block this process.
Very effective in the treatment of PUD. Very easy to administer (use) If administer for 6 to 8 weeks, H2 blocker can
heal duodenal ulcer 75% and 90% respectively. Can be given one single dose at bed time or two
divided dose
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H2 receptor antagonists continue
To treat duodenal ulcer or gasrtic ulcer for 6 to 8 weeks
Famotidine 40mg od or 20mg bid Nizatidine 300mg od or 150mg bid Ranitidine 300mg od or 150mg bid Cimetidine 800mg od or 400mg bid
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H2 receptor antagonists continue
Rapidly absorb (1 to 3 hours to peak) Bioavailability range from 30% to 88%
because of high first pass metabolism Nizatidine is 98%( availability) Ranitidine and cimetidine hepatic
metabolism is the major pathway whereas famotidine and nizatidine is renally excreted. Some dose adjustment is needed in renal and hepatic failure patients
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H2 receptor antagonists continue
Adverse effects Diarrhea and constipation Mental confusion, dizziness,
headache Rash Cimetidine has antiandrogenic effect
cause gynecomastia and impotence Hepatotoxicity with rinatidine Most adverse effects seen in elderly
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H2 receptor antagonists continue
Drugs interaction
Increase serum levels of phenytoin, nifedipine, procanamide, theophylline, warfarin, benzodiazepine, carbamazapine, propanonol, qunidine.
Cytochrome P450 inhibition is highest with cimetidine
Nizatidine and famotidine has the least interaction.
Decrease the absorption of iron
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Proton Pump Inhibitors
Irreversibly bind to K+ _ H+ ATPase Total shut down of acid secretion Work at late in the acid production
cycle. Very effective in the treatment of PUD. Very easy to administer (use) If administer for 4 to 6 weeks, PPIs can
heal duodenal ulcer and gastric ulcer upto 90% .
Can be given one single dose at bed time or two divided dose
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Proton Pump Inhibitors continue
To treat duodenal ulcer or gasrtic ulcer for 4 to 6 weeks
Omeprazole 40 mg od or 20 mg bid Lansoprazole 60 mg od or 30 mg bid Pantaprazole 80 mg od or 40 mg bid
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Proton Pump Inhibitors continue
Unstable in acid media and granules are enteric coated
Rapidly absorb (2 to 4 hours to peak) Bioavailability range from 50% to 80% Omeprazole and lansoprazole are
prodrugs All of them work systemically (not locally) All of them are entirely metabolite in liver No dose adjustment is needed in renal
impairment and adjustment may be need in severe liver disease
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Proton Pump Inhibitors continue
Adverse effects
Nausea, abdominal discomfort, dizziness, headache
Increase liver enzymes
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Proton Pump Inhibitors continue
Drug interactions
PPIs bind to P450 oxidative enzymes Omeprazole decrease the
metabolism of diazepam, pheytoin, warfarin, tobutamide (increase the levels)
Lasoprazole is not shown to be interact with above drugs
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Sucalfate cytoproctective drugs
Bind to damaged and ulcerative tissue forming a physical barrier to injury from aggressive forces such as acid and pepsin
Not absorbed systemically Requires acidic media to be dissolve and
coated Can not be given with H2 blockers, PPIs,
Antacids or any acid suppressors Can not be given with food (must be given
one hour before meals or 3 hours after meals.
Very safe in pregnancy
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Sucalfate cytoproctective drugs
Can be given 1 gram 4 times daily or 2 gram 2 times daily.
As effective as H2 blockers Must be given for 6 to 8 weeks Large tablet and difficultly to swallow
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Sucalfate cytoproctective drugs
Adverse effects
Constipation, dry mouth, nausea, rashes
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Anacids neutralizing agent and cytoproctective
Neutralizing and cytoprotective effects Requires large amount of neutralizing capacity
(30cc one hour and three hours after the meals and bedtimes to heal the ulcers)
Very inconvenience to administer Very unpleasant taste Only use as needed to relieve ulcer pain in
conjunction with other acid suppressors such as H2 blockers and PPIs
Work within 5 to 15 minutes and duration of relieve last for 2 hours.
Liquid form is more effective than tablet form
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Anacids neutralizing agent and cytoproctective
Anacids contain either sodium bicarbonate, aluminum hydroxide, magnesium hydroxide, calcium carbonate
Sodium bicarbonate fast acting antacid by absorbs systemically and can cause alkalosis if use for long times
Aluminum hydroxide is always combine with magnesium or calcium because it is a weak antacid and cause constipation
Magnesium hydroxide antacid causes diarrhea and therefore need to combine with aluminum hydroxide
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Anacids neutralizing agent and cytoproctective
Small amount of antacid can be absorbed and not harmful if patient has good renal function
Avoid magnesium containing antacid in renal failure patient
Calcium carbonate containing antacids work rapidly and very effective but large dose may cause gastric acid secretion and calciuria
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Anacids neutralizing agent and cytoproctective
Antacids alter gastric pH and interfere with the absorption of many drugs. (digoxin and phenytoin, ketoconazole)
Decrease the bioavailability of cimetidine by 50%, ranitidine and famotidine by 30% if take together with antacids.
May dissolve enteric coated tablets at stomach which suppose to be dissolve at somewhere else.
Decrease antibiotics absorption (ciprofloxacin by 50% and tetracycline etc)
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Relapse Rate
Duodenal Ulcer
One Year
80% to 90%
Two Year
100%
Gastric Ulcer 70%
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NSAIDS
Symptomatic GI ulceration occurs in 2% - 4% of patients treated with NSAIDs for 1 year
In view of the million of people who take NSAIDs annually, these small percentages translate into a large number of symptomatic ulcers
The effects of aspirin & NSAIDs on the gastric mucosa ranges from mucosal hemorrhages to erosions & acute ulcers
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NSAIDS
Inhibits the production of Inhibits the production of prostaglandinsprostaglandins
precursor from membrane fatty acids resulting precursor from membrane fatty acids resulting
in:in:
1. Decrease mucus & HCO3 production1. Decrease mucus & HCO3 production
2. Decrease mucosal blood flow2. Decrease mucosal blood flow
3. Reduce cell renewal3. Reduce cell renewal The drugs also generate oxygen-free radicals &
products of the lipoxygenase pathway that may contribute to ulceration
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PATHOGENESIS OF NSAID-INDUCED GASTROPATHY
Because most NSAIDs are weak acids, they are present in unionized forms in the acidic environment of the stomach.Presence of the drug in this form facilitates diffusion across the GI epithelial cells, with subsequent ionization within the neutral intracellular environment. The ionized form of the drug is then incapable of diffusing out of the cell, a process known as “ion trapping”. As the drug accumulates within the cell, the osmotic gradient produced results in an influx of water causing swelling and eventually cell lysis.
Pharmacotherapy Self Assessment program, 5th Edition NSAID-induced Gastropathy
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PATHOGENESIS OF NSAID-INDUCED GASTROPATHY
Pharmacotherapy Self Assessment program, 5th Edition NSAID-induced Gastropathy
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RISK FACTORS FOR UPPER GI COMPLICATIONSAIN PATIENTS RECEIVING NSAIDS
RISK FACTORS FOR UPPER GI COMPLICATIONSAIN PATIENTS RECEIVING NSAIDS
Risk Factor Odd ratio
RA (vs. OA) 1.5
Low-dose aspirin use alone (< 160 mg/day) 1.6
Corticosteroids 1.6
Age 50–59 years 2.4
Use of nonaspirin (nonselective) NSAID alone 4.1
Age 60–69 years 3.1
Age 70–80 years 4.5
Aspirin (75–160 mg/day) 5.6
History of uncomplicated ulcer 5.9
Use of more than nonaspirin NSAID daily 9.0
Age older than 80 years 9.2
Anticoagulation 12.7
History of complicated ulcer 15.4Pharmacotherapy Self Assessment program, 5th Edition NSAID-induced Gastropathy
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RISK FACTORSRISK FACTORS
The annual incidence of NSAID-related ulcer complications based on:
the number of risk factors present is about 0.8% in patients with no risk factors.
•2% for one risk factor.
•7.6–8.6% for three risk factors.
•18% for four risk factors.
Pharmacotherapy Self Assessment program, 5th Edition NSAID-induced Gastropathy
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RISK FACTORSRISK FACTORS
• Low risk (absence of any risk factors).
• Moderate risk (one or two risk factors)
• High risk (more than two risk factors or concurrent use of aspirin, corticosteroids, or warfarin)
• Very high risk (more than three risk factors or a history of recent ulcer complication).
Pharmacotherapy Self Assessment program, 5th Edition NSAID-induced Gastropathy
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Type of NSAID & Risk of UlcerType of NSAID & Risk of Ulcer
Risk Group Drug Relative Risk
Low Ibuprofen
Diclofenac
2.0
4.2
Medium Naproxen
Indomethacin Piroxicam
9.1
11.3
13.7
High Ketoprofen Azapropazone
23.7 31.5
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Recommendations for H.pylori Testing & Eradication in NSAID Users
Recommendations for H.pylori Testing & Eradication in NSAID Users
1- Patients who have a history of ulcer complication should undergo H. pylori testing. H. pylori should be eradicated in all infected patients because it is not possible to determine whether the ulcer complications were caused by NSAIDs or both.
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H. Pylori and Low Dose Aspirin (LDA) H. Pylori and Low Dose Aspirin (LDA)
• Eradication of H. pylori infection lower the risk of ulcer recurrence in patients on LDA or NSAIDs
• Treatment with a PPIs in addition to the eradication of H. pylori can significantly reduce the risk of recurrent ulcer complications if LDA or NSAIDs continue
N Engl J Med 2001 Mar 29;344(13):967-73. N Engl J Med 2002 Jun 27;346(26):2033-8.
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Association between Gastric Ulcer and
Pylori
NSAIDS
H Pylori
Cancer
Slice 472%
26%
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Association between DU and H Pylori
H Pylori
NSAID
Cancer
Other
92%
5%
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Characteristics of H Pylori
Spiral or curve shape gram negative rod with flagella Unique ability to colonize the stomach Located on epithelial cell within the mucus layer
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Pathogenic properties of H Pylori
Colonizationfactors
Persistencefactors
Disease inducingfactors
Urease productionSpiral shape (motility adhesions)
LPSUREASE
Vacuolating cytotoxitc Catalise Phospholipase
LMW Chemotactic protein Urea
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Risk of developing duodenal ulcer
Cag A
Vac A
65% H Pylori
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Mode of Transmission
Fecal Oral Water borne
Oral Oral Spouses Dental plaque endoscope
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0
20
40
60
80
100
%
10 20-29
40-49
<60
Age
Age specific prevalence of H Pylori
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Prevalence of H Pylori in developed and developing countries
0
20
40
60
80
100
10 20 30 40 50 60 70 80
age
%
rapid acq
low incid
none
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Factors associated with H Pylori infection
Low socio-economicstatus
Crowded livingconditions
Geographiclocation/E
thnicgroup
Increasingage
Gastroenterolosist
Dentist
H Pyloriinfection
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Effects of socio-economic status
0102030405060708090
%
Low Med High
socio- economic status
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H Pylori distribution according to crowding index
0
10
20
30
40
50
60
70
%
High Mid Low
crowding index
East
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Available Test For H Pylori Infection
Office test
Tests at endoscope
Serology TestUrea Breath Test
Biopsy urease testHistologyCulture
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Diagnosis of H. pylori
Non-invasive C13 or C14 Urea Breath Test Stool antigen test H. pylori IgG titer (serology)
Invasive Gastric mucosal biopsy Rapid Urease test
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Diagnosis of H. pylori
Non-invasive 1. C13 or C14 Urea Breath Test
The best test for the detection
of an active infection
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Diagnostic Tests for Helicobacter pylori Noninvasive
Test Sensitivity (%)
Specificity (%)
Usefulness
Urea breath test 95 to 100 91 to 98 Requires separate appointments; sensitivity reduced by PPIs, antibiotics, & bismuth-containing compounds; reliable test for cure.
Best available noninvasive test in children but higher false +ve rates in infants & children younger than six years compared with school-age children & adolescents
ABLES A Z et al. American Family Physician. 2007
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Diagnosis of H. pylori
Non-invasive 1) Serology for H pylori
a. Serum Antibodies (IgG) to H pylori (Not for active infection)
b. Fecal antigen testing (Test for active HP)
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Diagnosis of H. pylori
Invasive Upper GI endoscopy
Highly sensitive test Patient needs sedation Has both diagnostic & therapeutic role
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Diagnosis of H. pylori
Invasive (endoscopy)– Diagnostic: Detect the site and the size of the ulcer,
even small and superficial ulcer can be detected
Detect source of bleeding Biopsies can be taken for rapid urease
test, histopathology & culture
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Diagnosis of H. pylori
Invasive (endoscopy) Rapid urease test ( RUT)
o Considered the endoscopic diagnostic test of choice
o Gastric biopsy specimens are placed in the rapid urease test kit. If H pylori are present, bacterial urease converts urea to ammonia, which changes pH and produces a CCOOLLOORR change
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Diagnosis of H. pylori
Invasive (endoscopy)* Histopathology
o Done if the rapid urease test result is negative
* Cultureo Used in research studies and is not
available routinely for clinical use
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Definition
Eradication H Pylori is undetectable after 4 weeks of treatment.
Recurrent H Pylori is detectable after 4 weeks of stopping the therapy
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Management of H pylori InfectionChallenge We Face
Ahmed Mayet, Pharm.D.,BCPSAssociate Professor
KSU
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One out of ten Americans suffers from peptic ulcer disease during their lifetime.
Ulcers cause an estimated 1 million hospitalizations and 6500 deaths per year.
Annual health care costs of PUD have been estimated at nearly $6 billion.
Burden of PUD on Heath Care System
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Burden of PUD on Heath Care System
$3 billion in hospitalization costs, $2 billion in
physician office visits, and $1 billion in decreased
productivity and days lost from work.
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Causes of PUD
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H.Pylori as a Cause of PUD
95%70%
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H pylori Infection
~ ½ of the world’s population carries the organism.
Prevalence varies widely:
> 80% of adults in Japan & South America
~ 40% in United Kingdom
~ 20% in Scandinavia
Fuccio et al, BMJ 2008; 337: 746-750
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Indications based on Maastricht consensus report 2000 :
Peptic ulcer disease
Mucosa-associated tissue lymphoma (MALT)
Atrophic gastritis
Post-gastric cancer resection
First degree relatives of gastric cancer patients
Idiopathic Thrombocytopenic Purpura
Who Need H. Pylori Eradication
Maastricht consensus report 2000
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Non-invasive:C13 or C14 Urea Breath Test
Stool antigen test
H. pylori IgG titer (serology)
Invasive: (Gastric mucosal biopsy )Rapid Urease test
Histopathology
Diagnosis of H. pylori
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Why Treat H pylori Infection ?
Disease or condition Benefit
Peptic ulcer (active or healed)Healing; prevention of recurrence;
prevention of recurrent bleeding
Gastric mucosa associated lymphoid
tissue lymphoma (MALT low grade)Durable remission
Uninvestigated dyspepsiaManagement of dyspepsia
symptoms
Patient at increased risk of gastric cancer (1st degree relative of patient with gastric cancer and after gastric cancer resection)
Prevention of development or
recurrence of non-cardia gastric
cancer
Fuccio et al, BMJ 2008; 337: 746-750
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Expected Outcomes of H pylori Therapy
In 1997, the Masstricht conferences defined the breakpoint between acceptable & unacceptable therapy as intention-to-treat eradication rate of > 80%
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Expected Outcomes of H pylori Therapy
Grading scale for H pylori therapy
Graham et al, Drugs 2008; 68 (6): 725-736
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OR
Eradication Therapy
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If FailureSalvage Therapy
H Pylori Treatment Regimens
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Traditional Regimens:Triple Therapy
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Optimal duration: 7,10,or 14 days (controversial)
A meta analysis found that 10 days 4% in eradication 14 days 5% in eradication
Traditional Regimens:Triple Therapy
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Is Triple Therapy Still Effective ?
Results of recent comparative studies with >100 patients that tested the combination of a PPI + amoxicillin + clarithromycin.
Graham et al, Drugs 2008; 68 (6): 725-736
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A randomized trial in Japan highly effective (>90% eradication rate) for metronidazole sensitive strains
Vakil N, Am J Gastroenterol 2009; 104:26-30
Traditional Regimens: Alternative Triple Therapy
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Why Does Eradication Therapy Fail ?
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Why Does Eradication Therapy Fail ?
Vakil N, Am J Gastroenterol 2009; 104:26-30
Resistance is one of the main causes
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Why Does Eradication Therapy Fail ?
In USA, of 347 clinical H pylori isolates collected b/w Dec. 1998 & 2002:
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Why Does Eradication Therapy Fail ?
Antimicrobial susceptibility pattern of H. pylori strains in Saudi Arabia and particularly in the western region (A total of 1104 gastric biopsies)
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Why Does Eradication Therapy Fail ?
Clarithromycin resistance is the strongest predictor of treatment failure.
When clarithromycin resistance reaches 15-20% eradication rate will be less than the recommended threshold of 80%.
Resistance
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Why Does Eradication Therapy Fail ?
Metronidazole resistance does not significantly affect the outcome of therapy.
A higher dose of metronidazole effectiveness in metronidazole-resistant H pylori.
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Eradication Failure Metronidazole Resistance
Study of 92 Pts with H. pylori infection Failed 1st line therapy PPI + Amoxicillin + Clarithromycin, antibiotic sensitivity testing was performed and Metronidazole resistance was present in 26%.
Pts received 2nd line therapy PPI + Amoxicillin + Metronidazole ER was: 97% of those who were Metronidazole sensitive 82% of those who were Metronidazole resistant
American Family Physician. 2007
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Eradication Failure Metronidazole Resistance
In vitro resistance to metronidazole may not accurately reflect in vivo resistance
Fuccio et al, BMJ 2008; 337: 746-750
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Eradication Failure Clarithromycin Resistance
In a retrospective analysis of antimicrobial resistance 53 pts received clarithromycin-based regimens and 13 had clarithromycin resistance.
ER: 87% of those who were clarithromycin sensitive 23% of those who were clarithromycin resistant
American Family Physician. 2007
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Testing for antimicrobial susceptibility has several limitations:
In vitro resistance to metronidazole may not accurately reflect in vivo resistance
Expensive
Not done routinely in most hospitals
Performed on gastric biopsies
Expensive, not well tolerated ,not indicated in several circumstances
Is antimicrobial susceptibility testing essential to H pylori eradication ?
Fuccio et al, BMJ 2008; 337: 746-750
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Sensitivity Testing
Benefit of antibiotic sensitivity testing before 1st-line H. pylori eradication: the studies, results
showed insignificant difference between empirical versus sensitivity testing
groups
Benefit of antibiotic sensitivity testing before 2nd-line H. pylori eradication: the studies, results
showed significant difference between empirical versus sensitivity testing groups
Fuccio et al, BMJ 2008; 337: 746-750
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In current clinical practice, the role of antimicrobial susceptibility testing is likely to be marginal or not recommended.
Is antimicrobial susceptibility testing essential to H pylori eradication ?
Fuccio et al, BMJ 2008; 337: 746-750
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Sensitivity Testing Before 2nd-line Treatment
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Sensitivity Testing Before 2nd-line Treatment
OAC7 = PPI bd+amoxicillin 1 gbd+ clarithromycin 500 mg bd 7 days
OAC14 = PPI bd+amoxicillin 1 g bd+clarithromycin 500 mg bd 14 days
OAM14 = PPI bd,amoxicillin 1 g bd,and metronidazole 500 mg bd for 14 day
STG = Susceptibility testing group.
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Recurrence rates worldwide vary but lower in developed countries.
In the primary care setting, physicians should choose an alternative eradication regimen for recurrences infection, depending on risk factors.
It is too early to know whether shorter courses of eradication therapy is associated with a higher resistance rate
Recurrence
American Family Physician. 2007
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Risk factors for recurrence include:Non-ulcer dyspepsia
Persistence of chronic gastritis after eradication therapy
Female gender
Intellectual disability
Younger age
High rates of primary infection
Higher urea breath test values
Recurrence
American Family Physician. 2007
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Traditional Regimens: Quadruple Therapy
•Efficacy remains above 80% when clarithromycin resistance is between 15-20%
• Eradication rate 93% in Europe and 87.7% in USA for 10-day therapy (ITT).
• Optimal duration: 10-14 days
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Type Mild Moderate Severe
Nausea ++++ ++++ +
Vomiting +++ +++ +
Loose stools +++ +++ +
Diarrhea ++ +
Metallic taste ++++ ++++ +
Rash + +
Malaise + +
Headache + +
Side effects from Quadruple Therapy (Bismuth)
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Compliance > 60 %
Compliance < 60 %
Effect of compliance on eradication ofH Pylori using Quadruple therapy (Bismuth)
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Emerging Initial Treatment Regimens
Amoxicillin 100 mg BID
+ clarithromycin 250 mg BID
+ metronidazole 400 mg BID
+
PPI BID
Non-bismuth quadruple therapy
Graham et al, Drugs 2008; 68 (6): 725-736
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Emerging Initial Treatment Regimens:Sequential Therapy
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11 randomized trials.
Eradication rates (ITT):Sequential vs. 7-day triple therapy 93.5% vs. 76.1%Sequential vs. 10-day triple therapy 92.4% vs. 79.2%
3 abstracts included, but excluding them did not alter conclusions.
Tong et al, J Clin Pharm Ther 2009; 34: 41-53
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All the studies come from Italy.
Many studies have limitations (sample size, blinding).
Tong et al, J Clin Pharm Ther 2009; 34: 41-53
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Salvage Therapies
Aliment Pharmacol Ther 2006; 23:35-44
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Levofloxacin 250 mg BID + Amoxicillin 1 gm BID + PPI BID
8 studies compared levofloxacin-based triple therapy with quadruple therapy for treatment failure.
Salvage Therapies
Gisbert et al, Aliment Pharmacol Ther 2006; 23:35-44
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Eradication rate with levofloxacin 81% vs. 70% (OR 1.8, 95% CI= 0.94-3.46) (heterogeneity present).
The difference was statistically significant when a single outlier study was removed (OR 2.2, 95% CI= 1.3-3.9).
Gisbert et al, Aliment Pharmacol Ther 2006; 23:35-44
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10-day regimen more effective than 7-day regimen (81% vs. 73%, P < 0.01)
Levofloxacin regimen was better tolerated than quadruple therapy (adverse effects 19% vs. 44%)
Levofloxacin resistance reached high levels in some areas may no longer be an acceptable salvage regimen in those areas
Gisbert et al, Aliment Pharmacol Ther 2006; 23:35-44
Salvage Therapies
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Salvage Therapies
Gisbert et al, Aliment Pharmacol Ther 2006; 23:35-44
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Vakil N, Am J Gastroenterol 2009; 104:26-30
Salvage Therapies
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Leukopenia with rifabutin in 25%, myalgia with levofloxacin in 30%
Resistance to rifabutin-like drugs is still quiet low (<5%)
Vakil N, Am J Gastroenterol 2009; 104:26-30
Salvage Therapies
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Salvage Therapies
Gisbert et al, Aliment Pharmacol Ther 2006; 23:35-44
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Low cost
Lack of resistance
Not widely available in Europe & western countries
High doses side effects (diarrhea)
Data on efficacy not consistent no definitive conclusions.
Salvage Therapies
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Systematic reviews have concluded that the urea breath test is the test of choice (sensitivity and specificity exceed 95%)
Eradication of H pylori should be confirmed at least four weeks after treatment ends.
How can eradication be confirmed ?
Fuccio et al, BMJ 2008; 337: 746-750
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It is unclear whether testing to confirm eradication is worthwhile in all patients.
Patients with H. pylori-associated peptic ulcer bleeding should be tested to confirm eradiation after completion of antibiotic treatment.
Is confirmation of H. pylori after eradiation with antibiotic treatment needed?
Aliment Pharmacol Ther. 2005;22:529-37.
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Do we need to screen and eradicate H pylori to prevent
gastric cancer?
Epidemiologic evidence suggests that infection with HP is
associated with >2 fold increase risk of gastric cancer.
However, wide-spread screening for H pylori in
asymptomatic individuals cannot be recommended at this
time
Gastric Cancer and H. pylori
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Current recommendation is Persons at high risk for gastric cancer (first degree
relatives) should be screened and eradicate if H pylori is positive.
American Family Physician. 2007
Gastric Cancer and H. pylori
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What shall we do in patient with early gastric cancer and positive for H pylori?
In a large-scale multicenter Japanese study, patients who had received endoscopic treatment (surgery) for early gastric cancer were randomized to H pylori eradication and non-eradication groups for investigation of cancer recurrence.
After 3 years of followed up, cancer recurrence was markedly reduced in the eradication group.
Gastric Cancer and H. pylori
Helicobacter 2010 feb 15 (1) 1-20 Lancet 2008;372:392–7.
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It is recommended that H pylori infection must be eradicated after the surgery of gastric cancer or in patient with athrophic gastritis.
Gastric Cancer and H. pylori
Helicobacter 2010 feb 15 (1) 1-20 Lancet 2008;372:392–7.
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Do we need to eradicate H pylori in patient with MALT lymphoma?
H pylori eradication leads to histologic and endoscopic improvement, as well as regression of MALT lymphoma in 60–80% of H.pylori-positive patients.
H.pylori eradication therapy should be the treatment of choice in such patients. (Evidence level III)
Gastric MALT lymphoma and H pylori
Lancet 1998;342:568. Lancet 1995;345:1591–4.
MALT= Gastric mucosa associated lymphoid tissue lymphoma
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Does H. pylori need to be eradicated in NSAIDs users with history of ulcer complication?
Recommendations:
1- Patients who have a history of ulcer complications (bleeding ulcer) should undergo H. pylori testing and should be eradicated in all infected patients because it is not plausible to determine whether the ulcer complications were caused by NSAIDs (including low dose aspirin) or both.
2- In addition, continuous PPIs prophylaxis is recommended such patients.
. .
H.pylori Testing and eradication in NSAID Users
N Engl J Med 2002 Jun 27;346(26):2033-8
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Does H. pylori need to be eradicated in naive NSAIDs users without history of ulcer complication?
There is a benefit from screening for H. pylori in naive NSAID users at the start of therapy and eradicate if it is positive. It will lower the prevalence of ulcer.
When compared with PPIs prophylaxis, the preventative effects of H. pylori eradication is inferior.
H. Pylori and NSAIDs
Lancet 2002 Jan 5;359(9300):9-13. Aliment Pharmacol Ther 2005;21:1411–8.
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Recommendations
Eradication of H. pylori infection is not always recommended for patients taking NSAIDs but PPIs prophylaxis is recommended in high risk patient.
H. Pylori and NSAIDs
Lancet 2002 Jan 5;359(9300):9-13. Aliment Pharmacol Ther 2005;21:1411–8.
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A meta-analysis of 17 studies revealed a signicant increase of the platelet count after H.pylori eradication therapy and improvement of the platelet count is maintained or increased due to eradication therapy.
H.pylori eradication should be the treatment of choice for H.pylori-positive patients with chronic ITP (Evidence level I)
Idiopathic Thrombocytopenic Purpura
Ann Hematol 2003;82:30–2. Am J Med 2005;118:414–9.
Helicobacter 2004;9:443–52. J Gastroenterol Hepatol 2007;22:2233–7.
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Eradication therapy is strongly recommended in the Mastricht III Consensus report for patients with H.pylori positive functional dyspepsia* based on significant efficacy shown by a number of meta-analyses .( Evidence level I)
H.Pylori Eradication for Functional Dyspepsia
Gut 2007;56:772–81 Am J Gastroenterol 2007;102:1808–25.
*Absence of any organic disease that can explain the symptoms.
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