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PEPTIC ULCERS
PEPTIC ULCERS
Definition: Chronic peptic ulcers are defects in the gastric (gastric ulcer) or
duodenal (duodenal ulcer) mucosa that require gastric acid for their formation.
Chronic peptic ulcers differ from erosions and gastritis in that the ulcer extends
deeper into the muscularis mucosa
Pathophysiology
1. Relief of pain
2. Reduce acid secretion
3. Promotion of epithelial healing
4. Prevention of ulcer recurrence
5. Eradication of H. pylori is an additional outcome.
A. Life -style Changes
1. Discontinue NSAIDs and use Acetaminophen for pain control if
possible.
2. Smoking cessation
3. Stress reduction
4. Spices reduction
B. Strategy for the treatment of peptic ulcer are:
1. Reduction of gastric acid secretion
A. Antihistamines H2 : Cimetidine, Ranitidine, Famotidine, Roxatidine
B. Proton pump inhibitors(PPIs): Omeprazole, Lansoprazole,
Pantoprazole, Rabeprazole, Esomeprazole, Dexlansoprazole
C. Anticholinergics: Pirenzepine, Propantheline, Oxyphenonium
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D. Prostaglandin analogue PGE2&PGI2: Misoprostol
2. Neutralization of gastric acid (Antacids)
A. Systemic: Sodium bicarbonate, Sod. Citrate and Calcium carbonate
B. Nonsystemic: Magnesium hydroxide, Mag. trisilicate, Aluminium
hydroxide gel, Magaldrate.
3. Ulcer protectives: Sucralfate, Colloidal bismuth subcitrate (CBS)
4. Anti-H. pylori drugs: Amoxicillin, Clarithromycin, Metronidazole,
Tinidazole, Tetracycline
Antihistamine (H2) Examples ,Cimetidine, Famotidine ,Ranitidine and
Nizatidine
Pharmacokinetics of Antihistamine
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1. Headache, dizziness, bowel upset, dry mouth, rashes.
2. CNS effects like confusional state, restlessness, convulsions and coma
3. Bolus i.v. injection can release histamine → bradycardia, arrhythmias
and cardiac arrest: it should always be given by slow infusion
4. Transient elevation of plasma aminotransferases; but hepatotoxicity is
rare
5. Cimetidine (but not other H2 blockers) has antiandrogenic action
(displaces dihydrotestosterone from its cytoplasmic receptor)→↑ plasma
prolactin and inhibits degradation of estradiol by liver. High doses given
for long periods have produced gynaecomastia, loss of libido, impotence
and temporary decrease in sperm count.
Drug interaction of antihistamine
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Bioavailability of all PPIs is reduced by food except dexlansoprasole ;
they should be taken in empty stomach, followed 1 hour later by a meal to
activate the H+K+ ATPase and make it more susceptible to the PPI.
Although the plasma half-life of these agents~1-3 hrs , they have a long
duration of action due to covalent bonding with the H+/K+- ATPase
enzyme
PPIs undergo extensive first-pass metabolism in the liver, resulting in
various inactive metabolites that are excreted in the urine or bile.
No dose modification is required in elderly or in renal/hepatic
impairment.
Esomeprazole is the S isomer of omeprazole This isomer undergoes less
first-pass metabolism in the liver & has a lower plasma clearance as
compared with omeprazole
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5. DOC in Zollinger-Ellison syndrome( Definitive treatment is
surgical)
6. Aspiration pneumonia as an alternative to H2 blockers.
Side effects of Proton pump inhibitors
1. The most common side effects are nausea, abdominal pain, constipation
or diarrhea.
2. Rashes (1.5% incidence), leucopenia and hepatic dysfunction are
infrequent.
3. On prolonged treatment atrophic gastritis has been reported occasionally
4. Lately, few reports of gynaecomastia and erectile dysfunction, possibly due to
reduced testosterone level, on prolonged use of omeprazole have
appeared.
5. Muscle and joint pain
6. Accelerated osteoporosis among elderly due to reduced calcium
absorption
Long-term use of Proton pump inhibitors is associated with:
1. Low vitamin B12 levels (reduced absorption). Because acid is
required for its absorption in a complex with intrinsic factor.
2. Increase in risk of hip fractures (reduced Ca2+ absorption)
3. Increased risk of enteric bacterial infections: C. difficile infections;
Bacterial gastroenteritis.
4. Hypomagnesaemia and an increased incidence of pneumonia..
Note:
1. Lanoprazole is most potent PPI & is safest PPI in pregnancy.
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3. Omeprazole and esomeprazole may decrease the effectiveness of
clopidogrel because they inhibit CYP2C19 and prevent the conversion of
clopidogrel to its active metabolite
4. PPIs decrease absorption of calcium carbonate wheras Calcium citrate is
not affected
5. Clarithromycin inhibits omeprazole metabolism →↑its plasma
concentration
Atropinic drugs reduce the volume of gastric juice without raising its pH .
Stimulated gastric secretion is less completely inhibited
Effective doses (for ulcer healing) of nonselective antimuscarinics
(atropine, Propantheline, Oxyphenonium) invariably produce intolerable
side effects.
Introduction of H2 blockers and PPIs has sent them into oblivion
Prostaglandin analogs
1. Misoprostol (Cytotic ®)
Mechanism of action of Misoprostol
Inhibits secretion of HCl & stimulates secretion of mucus
& bicarbonate
In addition, PGE inhibit gastrin production, increase
mucosal blood flow
Uses of Misoprostol It is approved for prevention of ulcer induced by
NSAIDs
Side effects of Misoprostol Major problems in the use of
misoprostol are Diarrhoea, abdominal cramps, uterine bleeding,
abortion, and need for multiple daily doses. So that Patient
acceptability is poor
Contraindication of Misoprostol : In pregnancy since it can
stimulate uterine contractions and cause miscarriage.
2. Neutralization of gastric acid (Antacids)
A. Systemic: Calcium carbonate
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1) Sodium bicarbonate
Advantages of Sodium bicarbonate
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base disturbance occurs. However, small amounts that are absorbed have the
same alkalinizing effect as NaHCO3
1. Delayed Onset
2. All Mg salts have a laxative action by by generating osmotically active
MgCl2 in the stomach and through Mg2+ ion induced cholecystokinin
release
2) Aluminum hydroxide gel
Advantages
1. Delayed Onset
2. Constipation due to its smooth muscle relaxant Thus, it delays gastric
emptying. and mucosal astringent action.
3. Hypophosphatemia because Alum. hydrox. binds phosphate in the
intestine and prevents its absorption
4. If renal impairment encephalopathy myopathy due to bismuth toxicity
5. Osteomalacia(↓phosphate absorption)
Combination: Magaldrate (Mg(OH)2 +Al(OH)3) salts can avoid these side effects
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1) Fast (Mag. hydrox.) and slow (Alum. hydrox.) acting components yield
prompt as well as sustained effect.
2) Mag. salts are laxative, while alum. salts are constipating: combination
may annul each other’s action and bowel movement may be least affected.
3) Gastric emptying is least affected; while alum. salts tend to delay it,
mag./cal. salts tend to hasten it.
4) Dose of individual components is reduced; systemic toxicity (dependent on
fractional absorption) is minimized.
Uses of Antacid :
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Ulcer protectives
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Note: Sucralfate is infrequently used now because of need for 4 large well-
timed daily doses and the availability of simpler and more effective H2
blockers/PPIs.
Interactions of Sucralfate
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2. bismuth subsalicylate is used in Traveller’s diarrhea. It reduces stool
frequency by inhibiting PG synthesis and chloride secretion apart from
having antimicrobial and gastro protective effects.
Treatment of H. pylori–Associated Ulcers
The goal of H. pylori therapy is to eradicate the organism using an effective
antibiotic-containing regimen. Reliance on conventional acid-suppressive drug
therapy alone as an alternative to H. pylori eradication is inappropriate because it is
associated with a higher incidence of ulcer recurrence and ulcer related
complications. Reinfection rates are generally low after the initial course of
therapy as long as the patient was adherent. The selected H. pylori regimen
should have a per-protocol cure rate of 90% or more or a cure rate based on
intention-to-treat analysis of 80% or more. In addition to proven efficacy, the
optimal treatment regimen should cause minimal adverse events, have low risk
for development of bacterial resistance, and be cost-effective.
H. pylori treatment regimens are presented in Table 18–2. Eradication therapy
with a PPI based three-drug regimen should be considered for all patients who test
positive for H. pylori and have an active ulcer or a documented history of either an
ulcer or ulcer-related complication. Different antibiotics should be used if a second
course of H. pylori eradication therapy is required. The cure rates of H. pylori with
H2RAs in combination with antibiotics are lower than with PPIs.
The first-line regimen should consist of triple drug therapy with a PPI plus
clarithromycin and either amoxicillin or metronidazole. Amoxicillin should not
be used in penicillin-allergic patients, and metronidazole should be avoided if
alcohol is going to be consumed. A single daily PPI dose may be less effective
than twice-daily dosing when used in a triple-drug regimen. Substitution of one
PPI for another is acceptable and does not affect eradication rates. Monotherapy
with a single antibiotic or antiulcer agent is not recommended due to high failure
rates. In the United States, two-drug regimens consisting of a PPI and a single
antibiotic are also not recommended.
The duration of therapy for H. pylori eradication is controversial; US guidelines
recommend either 10 or 14 days. Compared with 7 days of triple therapy, a 10-
day duration increases eradication rates by 4% and 14 days increases
eradication rates by 5% to 12%.20,25 Longer treatment courses may decrease
adherence and increase drug costs; ultimately, the most effective eradication
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regimens still fail in 10% to 20% of patients. Bismuth-based four-drug regimens
have clinical cure rates similar to three-drug PPI-based regimens.
Bismuth-based regimens usually include a bismuth salt, tetracycline,
metronidazole, and an acid suppressing agent (PPI or H2RA). Bismuth salts
promote ulcer healing through antibacterial and mucosal protective effects.
Disadvantages of bismuth-based regimens include frequency of administration
(four times a day), risk for salicylate toxicity in renal impairment, and
bothersome side effects (eg, stool and tongue discoloration, constipation, nausea,
vomiting). Therefore, bismuth-based quadruple therapy is usually considered
second-line treatment.
Several combination products are available that may increase adherence to the
regimen. Pylera (bismuth subcitrate potassium 140 mg, metronidazole 125 mg,
and tetracycline 125 mg) combined with omeprazole 20 mg twice daily is as
effective as omeprazole–amoxicillin–clarithromycin in eradicating H. pylori in
patients with duodenal ulcers. The usual dose is three capsules four times daily
after meals and at bedtime with 8 oz (237 mL) water for 10 days.
Helidac is a package of 14 blister cards with each card containing a single-day
supply of bismuth subsalicylate (two 262.4-mg chewable tablets four times daily),
metronidazole (250-mg tablet four times daily), and tetracycline (500-mg capsule
four times daily). Unlike Pylera, Helidac is not a combination product; all
three medications must be taken four times daily for 14 days in combination with
an H2RA rather than a PPI. However, cure rates with H2RAs are less than with
PPIs and are therefore not preferred.
PrevPac contains lansoprazole 30 mg, amoxicillin 1 gram, and clarithromycin
500 mg; each agent is dosed twice daily. A study in patients with duodenal ulcer
showed comparable eradication rates with 10-day and 14-day regimens. Pylera,
Helidac, and PrevPac are substantially more expensive than the costs of their
individual generic and nonprescription components.
Patients may remain infected with H. pylori after the initial treatment course
because of reinfection, nonadherence, or antimicrobial resistance. Factors
associated with decreased adherence include polypharmacy, need for frequent
drug administration or long treatment duration, and use of drugs that may cause
intolerable side effects. Potential adverse drug effects include taste disturbances
(clarithromycin and metronidazole), nausea, vomiting, abdominal pain, and
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diarrhea. Superinfections with oral thrush or vaginal candidiasis can occur.
Alcohol should be avoided during treatment with metronidazole or tinidazole
due to the potential for a disulfiram-like reaction.
Preexisting antimicrobial resistance accounts for up to 70% of all treatment
failures and is most often related to metronidazole or clarithromycin.
Metronidazole-resistant strains are more prevalent in Asia (85%) than North
America (40%). Clarithromycin resistance rates are approximately 10% in the
United States. Although a threshold of 20% is recommended to differentiate
between regions of high and low clarithromycin resistance, triple therapy
regimens containing clarithromycin can begin to lose efficacy when resistance is
between 7% and 10%.Primary resistance to amoxicillin and tetracycline remains
low in both the United States and Europe.26 Culture and sensitivity studies
arenot routinely performed with H. pylori infection unless a patient has already
failed two different treatment regimens.
Initiation of a second H. pylori treatment regimen after failure of initial
treatment is usually associated with a lower success rate. Reasons for failure are
often the same as those reported with failure of the initial regimen. In these
situations, quadruple therapy for 14 days is generally required, and
metronidazole or clarithromycin should be replaced by another antibiotic if
either one of these agents was used in the initial regimen.26 If both
clarithromycin and metronidazole were used as initial therapy, a regimen
consisting of amoxicillin 1 g twice daily, levofloxacin 250 mg twice daily, and a
PPI twice daily may be used for 10 to 14 days.28 Another salvage therapy
consisting of amoxicillin 1 g twice daily, rifabutin 150 mg twice daily, and
ciprofloxacin 500 mg twice daily for 14 days is also effective, but patients
receiving this regimen experienced more adverse effects.
There is no standard third-line therapy for H. pylori treatment. If the patient was
adherent with initial treatment, then culture and sensitivity testing should be
completed in order to select an antimicrobial regimen with adequate sensitivities.
Sequential therapy is a possible alternative 10-day regimen that may also be used
to treat H. pylori infection and consists of using different combinations of
antibiotics for 5 days each in addition to a PPI twice daily. Eradication rates are
reported to be between 85% and 90%.
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Several additional modifications to treatment regimens have been proposed.
Modified triple therapy containing levofloxacin may be considered in
populations with high clarithromycin resistance; eradication rates range from
72% to 96%. The standard sequential therapy regimen has also been modified
by replacing clarithromycin with tetracycline with variable results. Lastly,
concomitant four-drug regimens and hybrid (sequential concomitant) therapy
have also been evaluated. One study comparing sequential versus concomitant
regimens using a PPI, amoxicillin, clarithromycin, and metronidazole showed
similar eradication rates (92.3% and 93%, respectively) and may represent
options in the setting of antibiotic resistance.
Confirmation of H. pylori infection eradication is recommended in patients with
a history of H. pylori–associated ulcer, MALT lymphoma, resection for early
gastric cancer, and patients whose symptoms persist after H. pylori treatment for
dyspepsia.
Eradication may be confirmed by either the urea breath test or stool antigen
testing. Eradication may also be confirmed by endoscopy, but this should only be
done when endoscopy is required because it is more expensive and invasive.
Treatment of NSAID-Induced Ulcers
Treatment recommendations to heal NSAID-induced ulcers or provide
maintenance therapy in patients receiving NSAIDS are shown in Table 18–3.
Choice of regimen depends on whether NSAID use is to be continued. NSAIDs
should be discontinued and replaced with alternatives (eg, acetaminophen), when
possible. For patients who cannot discontinue NSAID therapy, PPIs, H2RAs, or
sucralfate are effective for ulcer healing and to prevent further recurrences. PPIs
are usually preferred because they provide more rapid relief of symptoms, have
the strongest acid suppression, and heal ulcers more quickly than H2RAs or
sucralfate. Standard doses of H2RAs effectively heal duodenal ulcers but are
minimally effective in gastric ulcers. In ulcers larger than 5 mm, the rate of ulcer
healing may be as low as 25% after 8 weeks of therapy with an H2RA.7 A PPI
provides equivalent efficacy with treatment duration of only 4 weeks. PPI
therapy should only be continued for longer than 4 weeks if an ulcer is
confirmed to still be present or if the patient develops severe complications from
PUD.
Prevention of NSAID-Induced Ulcers
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Prophylactic regimens against PUD are often required in patients receiving long-
term NSAID or aspirin therapy for osteoarthritis, rheumatoid arthritis, or
cardioprotection.33 Misoprostol, H2RAs, PPIs, and COX-2 selective inhibitors
have been evaluated in controlled trials to reduce the risk of NSAID-induced
PUD. In patients at risk for NSAID-induced ulcers, PPIs at standard doses reduce
the risk of both gastric and duodenal ulcers as effectively as misoprostol and more
effectively than H2RAs. In addition, PPIs are generally better tolerated than
misoprostol.
Prevention of Stress-Related Mucosal Damage
Prevention of stress ulcers involves maintaining hemodynamic stability to
maximize mesenteric perfusion and pharmacologic suppression of gastric acid
production. Stress ulcer prophylaxis is only indicated in intensive care unit
(ICU) patients with certain risk factors (see Table 18–4).
Appropriate Indications for Stress Ulcer Prophylaxis in Intensive Care Unit
Patients
1. Mechanical ventilation for longer than 48 hours
2. Coagulopathy or hepatic failure (platelet count < 50 × 103/mm3
3. (50 × 109/L), INR > 1.5, or aPTT > two times control)
4. History of GI ulceration or bleeding within 1 year of admission
5. Head trauma or Glasgow Coma Score of 10 or less (or inability to obey
simple commands)
6. Thermal injuries to more than 35% of body surface area
7. Multiple traumas (injury severity score of 16 or greater)
8. Partial hepatectomy
9. Transplant patients in the ICU perioperatively
10. Spinal cord injuries
11. Two of the following risk factors: sepsis, ICU stay for more than 1 week,
occult bleeding lasting 6 or more days, and use of high-dose
corticosteroids (> 250 mg/day of hydrocortisone or equivalent)
The clinician must weigh the risks and benefits of using acid suppression,
especially PPIs, in low-risk patients. PPIs and H2RAs are the drugs of choice for
SUP; however, antacids and sucralfate may be acceptable options in some
patients.
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Treatment of GI Bleeding
The immediate priorities in treating patients with a bleeding peptic ulcer are to
achieve IV access, correct fluid losses, and restore hemodynamic stability.
Insertion of a nasogastric tube is helpful in initial patient assessment, but the
absence of bloody or coffee-ground material does not definitively rule out
ongoing or recurrent bleeding; about 15% of patients without bloody nasogastric
tube output have a high-risk lesion at endoscopy.
Patients should be started on IV PPI therapy because optimal platelet
aggregation, partially inhibited fibrinolysis, and better clot stabilization on the
ulcer are achieved when the gastric pH is greater than 6. Intravenous PPI
therapy should be continued for 72 hours (because most rebreeding occurs
during this time) followed by oral PPI therapy. Three-day PPI infusion therapy
has been shown to be as effective as twice-daily IV PPI therapy.
Treatment of Refractory Ulcers
Refractory ulcers are defined as ulcers that fail to heal despite 8 to 12 weeks of
acid suppressive therapy.1 The presence of refractory ulcers requires a thorough
assessment, including evaluation of medication adherence, extensive counseling
and questioning regarding recent over-the-counter and prescription medication
use, and testing for H. pylori using a different method than previously done if
testing was negative. Changing from H2RA therapy to a PPI should be
considered.15 Other considerations include esophagogastroduodenoscopy (EGD)
with biopsy of the ulcer to exclude malignancy, H. pylori testing (if not done
initially), serum gastrin measurement to exclude ZES, and gastric acid studies.
Increasing the starting dose of PPI therapy may heal up to 90% of refractory
ulcers after 8 weeks of therapy.
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