3. Acid peptic disorders include a number of conditions
whose pathophysiology is believed to be the result of
damage from acid and pepsin activity in the gastric
secretions. This talk focuses on gastroesophageal
reflux disease (GERD) and peptic ulcer disease,
the two
most common and well-defined disease states.
4. Gastroesophageal reflux disease
Definition
GERD is defined as chronic symptoms of heartburn, acid
regurgitation, or both, or mucosal damage produced by
the abnormal reflux of gastric contents into the
esophagus.
Reflux esophagitis occurs in a subgroup of GERD patients
with histopathologically demonstrated characteristic
changes in the esophageal mucosa.
5. Pathophysiology
GERD occurs when the normal antireflux barrier between the stomach
and esophagus is impaired, either transiently or permanently.
Therefore, defects in the esophagogastric barrier , such as
lower esophageal sphincter incompetence ,
transient lower esophageal sphincter relaxation , and
hiatal hernia , are the primary factors involved in the development
of GERD.
Symptoms develop when the offensive factors in the gastroduodenal
contents, such as acid, pepsin, bile acids , and trypsin ,
overcome several lines of esophageal defense, including
esophageal acid clearance and mucosal resistance.
6. Signs and Symptoms
Classic symptoms of GERD are heartburn , defined as a
retrosternal burning discomfort, and acid regurgitation.
Symptoms often occur after meals and can increase when a
patient is recumbent .
Other ancillary symptoms seen in typical reflux are dysphagia,
odynophagia, and belching.
Atypical GERD symptoms include chest pain, asthma, cough,
hoarseness, sore throat, globus, and repetitive throat clearing.
7. Diagnosis
There is no diagnostic gold standard for this disease.
Classic symptoms of acid regurgitation and heartburn
are specific but not sensitive for the diagnosis of GERD,
as determined by abnormal 24-hour pH monitoring .
It is reasonable to consider an empirical trial of
antisecretory therapy in a patient with classic symptoms
of GERD in the absence of alarm signs.
8. Endoscopic evaluation should be performed under the
following conditions :
Failure to respond to an empirical course of
antisecretory therapy.
Alarm signs suggesting complicated reflux disease
(e.g., dysphagia, odynophagia, bleeding, weight loss,
anemia)
Chronic symptoms (>10 years) in a patient at risk for
Barrett's esophagus.
Patients requiring chronic antisecretory therapy.
9. Endoscopy is the technique of choice to evaluate the
mucosa in patients with symptoms of GERD.
Erosions or ulcerations at the squamocolumnar junction, as
well as the findings of Barrett's esophagus, are
diagnostic of GERD .
However, Barrett's epithelium must be confirmed by a
biopsy revealing intestinal metaplasia.
10. Treatment and Outcomes
The goals of treatment in GERD are
To relieve symptoms,
heal esophagitis ,
prevent recurrence of symptoms, and
prevent complications.
Lifestyle Modification
Various lifestyle modifications are recommended for the
treatment of GERD. Which include…
avoiding precipitating foods (e.g., fatty foods, alcohol,
caffeine),
avoiding recumbency for 3 hours postprandially,
elevating the head of the bed,
quitting smoking, and
losing weight.
11. Medication
The cornerstone of GERD therapy is the administration of agents
that decrease gastric acid secretion, thereby decreasing
esophageal acid exposure. An antacid , which only
neutralizes acid that is already secreted, Approximately 20%
of patients experience symptom relief with these therapies.
Administration of histamine-2 (H2) receptor antagonists
(H2RAs) in standard divided doses achieves complete
symptom relief in approximately 60% of patients and heals
esophagitis in about 50%.
PPIs are superior to H2RAs in regard to healing erosive
esophagitis and relieving symptoms, with healing rates
approaching 90% and symptom relief.
12. Because of their superiority in healing esophagitis and
maintaining symptom relief, PPIs are the treatment of
choice in patients with frequent reflux symptoms.
PPIs should always be given before meals ; a single
dose may be given in the morning to patients with daytime
symptoms and in the evening to those with nighttime
symptoms.
PPIs are generally well tolerated, with the most common
side effects being diarrhea and headache.
patients whose GERD is well controlled on PPI therapy
may consider step-down therapy to an H2 receptor
blocker.
13. Surgery(laproscopic fundoplication)sss
Antireflux surgery, now performed primarily by the laparoscopic
approach, remains an option for carefully selected patients
with well-documented GERD
Patients with predominant regurgitation symptoms, which are
often nocturnal,
evidence of ongoing acid exposure or esophageal damage while
PPIs are being used.
14. Cancer Prevention
Barrett's esophagus is a potentially serious complication of
chronic GERD. It is present when the normal stratified
squamous epithelium of the distal esophagus is replaced
by intestinal columnar metaplasia. It is the most significant
histologic outcome of long-standing GERD;
the odds of developing Barrett's epithelium increase by
about sixfold after 10 years of symptoms .
The most dreaded complication of Barrett's epithelium is
esophageal adenocarcinoma . However, the incidence
rate for developing esophageal carcinoma is still low, these
patients require not only acid suppression with PPIs to
control symptoms but also continued endoscopic
surveillance to detect the development of dysplasia and
adenocarcinoma.
15. Peptic ulcer disease
Definition
Peptic ulcers (gastric and duodenal) are defects in the GI
mucosa that extend through the muscularis mucosa.
Pathophysiology
Peptic ulcers are defects in the gastric or duodenal mucosa that
extend through the muscularis mucosa.
16. Phases of gastric secretion
Phase Stimuli Pathway
Cephalic (stimulate) Sight, smell, taste or 1) Vagus (M3 receptors)
thought of food 2) Histamine (H2 receptor)
3) Gastrin
Gastric (stimulate) Food in the stomach 1) Stretch: local reflex (M3
receptors)
2) Chemical substances in food
(gastrin)
3) Increase pH: Inhibition of
somatostatin (GHIH) release
Intestinal (inhibit) Chyme in the
duodenum
17. Mechanism of ulcer formation
High [H+] in the gastric lumen
Require defense mechanisms to protect
oesophagus and stomach
Oesophagus – LES
Stomach: a number of mechanisms
Mucus secretion: slows ion diffusion
Prostaglandins: I2 and E2 (alcohol, aspirin, and other
drugs)
Bicabonate ions
High Blood Flow (nitric oxide)
18. Under normal conditions, a physiologic balance exists between
peptic acid secretion and gastroduodenal mucosal defense.
thus, peptic ulcer occur when the balance between the
aggressive factors and the defensive mechanisms is
disrupted.
Aggressive factors, such as NSAIDs, H pylori , alcohol, bile
salts, acid, and pepsin, can alter the mucosal defense by
allowing back diffusion of hydrogen ions and subsequent
epithelial cell injury.
The defensive mechanisms include tight intercellular
junctions , mucus, mucosal blood flow, cellular restitution,
and epithelial renewal.
19. Imbalance
Imbalance primarily between Aggressive
factors and Defensive factors:
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20. Major Etiologies
Helicobacter pylori:
gram negative bacteria, can live in stomach and duodenum,
May breakdown mucus layer → inflammatory response to
presence of the bacteria also leads to ulcer
Gastric Acid:
needs to be present for ulcer to form → activates pepsin and
injures mucosa
Decreased blood flow: causes decrease in mucus
production and bicarbonate synthesis, promote
gastric acid secretion
NSAIDS: inhibit the production of prostaglandins
Smoking: nicotine stimulates gastric acid production
21. H. pylori
Gram (-) rod with flagella
H pylori is most common cause
of PUD
Transmission route fecal-oral
Secretes urease → convert urea
to ammonia
Produces alkaline environment
enabling survival in stomach
Almost all duodenal and 2/3
gastric ulcer pt’s infected with
HP
Considered class 1 carcinogen
→ gastric cancer
22. Gastric Ulcers
Common in late middle age
incidence increases with age
Male to female ratio — 2:1
Use of NSAIDs - associated with a three- to four-fold
increase in risk of gastric ulcer
Less related to H. pylori than duodenal ulcers
10 - 20% of patients with a gastric ulcer have a
concomitant duodenal ulcer
23. Duodenal Ulcers
Most common in middle age
peak 30-50 years
Male to female ratio — 4:1
Genetic link: 3x more common in 1st degree
relatives
H. pylori infection common
up to 95%
24. Signs and symptoms
History
Epigastric pain (the most common symptom)
Gnawing or burning sensation
Relieved by food or antacids
Patient awakens with pain at night.
May radiate to the back (consider penetration)
Duodenal ulcers : occurs 1-3 hours after a meal and may awaken
patient from sleep. Pain is relieved by food, antacids, or vomiting.
Gastric ulcers : food may increase the pain while vomiting relieves
it.
Nausea,Vomiting, which might be related to partial or complete gastric
outlet obstruction
Dyspepsia, including belching, bloating, distention, and fatty food
intolerance
Heartburn,Chest discomfort,Anorexia, weight loss
Hematemesis or melena resulting from gastrointestinal bleeding
Dyspeptic symptoms that might suggest PUD are not specific because
only 20-25% of patients with symptoms suggestive of peptic ulceration
are found on investigation to have a peptic ulcer.
25. Physical
In uncomplicated PUD, clinical findings are few and nonspecific.
Epigastric tenderness
Guaiac-positive stool resulting from occult blood loss
Melena resulting from acute or subacute gastrointestinal
bleeding
Succussion splash resulting from partial or complete gastric
outlet obstruction
26. Differential Diagnosis
Neoplasm of the stomach
Pancreatitis
Pancreatic cancer
Diverticulitis
Nonulcer dyspepsia (also called functional
dyspepsia)
Cholecystitis
Gastritis
GERD
MI—not to be missed if having chest pain
27. Investigations
Invasive
Endoscopic biopsy – demonstration of H-pylori in gastric mucosa
RIPID UREASE TEST
Non invasive
SEROLOGIC TESTS – IgG antibody response can be quantified
by ELISA
Urea breath test
28. Management
The management of patients with PUD needs to be
adapted to
• the specific clinical situation,
• etiology, and
• anticipated natural history.
The first steps in management are to identify
Helicobacter pylori (H. pylori) infection and users of
nonsteroidal antiinflammatory drugs (NSAIDs). Both
of these steps can be surprisingly difficult.
29. Markers of increased risk
A prior history of complications
A prior refractory or protracted course
Giant ulcers (>2 cm)
Presence of considerable depth or dense fibrosis, as suggested
by a deformed ulcer bed.
Medium-sized ulcers (1 to 2 cm) also deserve more caution than
ulcers less than 1 cm.
30. H. pylori-positive ulcers
Antibiotic therapy is clearly indicated if H. pylori is present in the
setting of any history of ulcer disease.
The goal of treatment in ulcers associated with H. pylori is to
"treat once successfully".
It is important to remember H. pylori ulcers recur within six
months in up to 20 percent of patients after apparently
successful antibiotic treatment.
31. Patients with a known ulcer history
The following are general principles to consider in patients
with prior or active ulcer disease, especially if complicated:
•NSAIDs should be avoided whenever possible in a patient with an
ulcer history.
•If NSAID use is unavoidable, they should be used at the lowest
possible dose and duration.
•Depending upon the timing and severity of the ulcer history,
misoprostsol or PPI cotherapy should be added if NSAIDs must be
used.
•Active ulcers should be treated with PPI and NSAIDs should be
stopped whenever possible.
•H. pylori should be sought and cured if present.
•Even when H. pylori has been successfully treated, PPI or misoprostol
cotherapy should be used in patients with prior ulcers if NSAID use
must be continued.
32. H. pylori-negative ulcers
H. pylori negative ulcers require special attention to
ensure that H. pylori infection has been excluded and
to detect NSAID use.
In confirmed non-H. pylori, non-NSAID ulcers, the first
consideration is excluding acid hypersecretory states,
such as
Zollinger-Ellison syndrome and
idiopathic non-H. pylori hypersecretory DU
(This is critical, especially if the ulcers are recurrent,
complicated, multiple, or in the distal duodenum)
33. Refractory ulcers
It is important to remember that many refractory cases,
even after prior failed surgery, are due to occult
consumption of aspirin and NSAIDs. The more
problematic the ulcer, the more critical the search for
surreptitious aspirin or NSAID use.
34. Peptic Ulcers
Therapy Purpose
Therapy is directed
at enhancing host
defense or
eliminating
aggressive factors;
i.e., H. pylori
35. Antacids
Weak bases that neutralize acid
Also inhibit formation of pepsin
(As pepsinogen converted to pepsin at
acidic pH)
Acid Neutralizing Capacity:
Potency of Antacids
Expressed in terms of Number of mEq of 1N
HCl that are brought down to pH 3.5 in 15
minutes by unit dose of a preparation (1 gm)
36. Antacids - The Oldest Remedy
Systemic-Sodium Bicarbonate:
Potent neutralizing capacity and acts instantly
ANC: 1 gm = 12 mEq
NOT USED ANYMORE FOR ITS
DEMERITS:
Systemic alkalosis
Distension, discomfort and belching – CO2
Rebound acidity
Sodium overload
37. Antacids
Present day antacids :
Buffer Type
Aluminium Hydroxide (ANC 1-2.5mEq/g)
Magnesium Hydroxide (ANC 30 mEq) – milk of
magnesia
Magnesium trisilicate (ANC 1mEq/g)
Magaldrate –hydrated hydroxy magnesiun aluminate
• Non Buffer Type
- Calcium Carbonate
38. Duration of action : 30 min when taken in empty stomach
and 2 hrs when taken after a meal
Side effects :
Aluminium antacids – constipation (As they relax gastric
smooth muscle ,delay gastric emptying & have
astringent
action) – also cause hypophosphatemia and
osteomalacia
Mg2+ antacids – Osmotic diarrhoea
In renal failure Al3+ antacid – Aluminium toxicity
& Encephalopathy
39. Antacids – contd.
Simethicone: Decrease surface tension
thereby reduce bubble formation - added
to prevent reflux
Alginates: Form a layer of foam on top of
gastric contents & reduce reflux
Oxethazaine: Surface anaesthetic
41. Sucralfate – ulcer protective
Salt of sucrose complexed to sulfated aluminium
hydroxide (basic aluminium salt)
MOA:
In acidic pH polymerises to viscous gel that adheres
to ulcer crater - more on duodenal ulcer
Precipitates protein on surface proteins and acts as
physical barrier
Dietary proteins get deposited on this layer forming
another coat
Delays gastric emptying and causes gastric PG
synthesis – protective action
42. Sucralfate
Taken on empty stomach 1 hr. before meals
Concurrent antacids, H2 antagonist avoided (as it
needs acid for activation)
Uses:
NSAID induced ulcers
Patients with continued smoking
ICU
Topically – burn, bedsore ulcers, excoriated skins
Dose: 1 gm 1 Hr before meals
ADRs: Constipation, hypophosphatemia ,inhibit
absorption of phenytoin,ketoconazole,cimetidine
43. H2 Antagonists
Cimetidine, Ranitidine, Famotidine, Roxatidine,
Nizatidine and Lafutidine
MOA:
Reversible competitive inhibitors of H2 receptor
Highly selective, no action on H1 or H3 receptors
All phases of gastric acid secretion
Very effective in inhibiting nocturnal(basal) acid secretion (as it
depends largely on Histamine )
Modest impact on meal stimulated acid secretion (as it depends
on gastrin, acetylcholine and histamine)
Volume of pepsin content and IF are also reduced
Volume reduced by 60 – 70% - anti ulcerogenic effect
No effect on motility
44. H2 antagonists
Kinetics:
All drugs are absorbed orally adequately
Bioavailability upto 80 %
Absorption is not interfered by presence of
food
Can cross placental barrier and reaches milk
Poor CNS penetration
2/3rd of the drugs are excreted unchanged in
bile and urine
Preparations: available as tablets,
injections
45. H2 antagonists - ADRs
Extremely safe drugs and well tolerated
Main ADRs are related to Cimetidine:
Antiandrogenic effects
Increases prolactin secretion and inhibits degradation of
estradiol by liver
Cytochrome P450 inhibition – theophylline, metronidazole,
phenytoin, imipramine etc.
Antacids
Others:
Headache, dizziness, bowel upset, dry mouth
Bolus IV – release histamine – bradycardia, arrhythmia, cardiac
arrest
Elderly - precaution
49. Lafutidine-a novel histamine H2 receptor
antagonist
Lafutidine is a novel histamine H2 antagonist with
gastroprotective activity.
Lafutidine exhibited potent and long-lasting H2
antagonism and prolonged antisecretion.
In addition, lafutidine showed a gastroprotective
effect against noxious agents-induced gastric mucosal
damage through capsaicin-sensitive afferent
nerves.
lafutidine is equal or superior to conventional H2
antagonists in antiulcer potency, and it may be useful for
the prevention of ulcer relapse and or treatment of
NSAIDs-induced gastroduodenal damage
50. Proton Pump Inhibitors Omeprazole
Most effective drugs in antiulcer therapy
Prodrugs requiring activation in acid
environment
Block enzymes responsible for secreting HCl -
binds irreversibly to H+K+ATPase
Prototype: Omeprazole
Examples:
Lansoprazole
Pantoprazole
Rabeprazole
Esomeprazole
51. Omeprazole - MOA
Substituted Benzimidazole derivative
Its a Prodrug
Diffuses into G. canaliculi = accumulation
pH < 5 (proton catalyzed )= tetracyclic sulfenamide +
sulphenic acid
Covalent binding with sulfhydryl cysteines of
H⁺K⁺ ATPase
Irreversible inactivation of the pump molecule
(The charged forms cannot diffuse back across the
canaliculi)
Lansoprazole partially reversible
Acid suppressants regardless of stimulating factors(80%-
90%)
52.
53. Pharmacokinetics - PPI
Oral forms are prepared as acid resistant formulations
that release the drug in the intestine (because they are
degraded in acid media)
After absorption, they are distributed by blood to parietal
cell canaliculi
They irreversibly inactivate the proton pump molecule –
but half life is very short and only 1-2 Hrs
Still action persists for 24 Hrs to 48 hrs after a single
dose – irreversible inhibition of PPI and new PP
synthesis takes time (24 to 48 hour suppression of acid
secretion, despite the much shorter plasma half-lives of
the parent compounds)
Platue state is attained after 4-5 days of dosing
Action lasts for 4-5 days even after stoppage of the drug
54. Pharmacokinetics - PPI
Given on an empty stomach because food affects
absorption
They should be given 30 minutes to 1 hour before food
intake because an acidic pH in the parietal cell acid
canaliculi is required for drug activation, and food
stimulates acid production
Concomitant use of other antisecretory drugs - H2
receptor antagonists – reduces action
Highly protein bound and rapidly Metabolized by the liver
by CYP2C19 and CYP3A4 – dose reduction necessary
in severe hepatic failure
Excreted in Kidneys minimally (no dose reduction
needed in renal failure and elderly)
55. Adverse Effects
The most common are GIT troubles in the form
of nausea, abdominal pain, constipation,
flatulence, and diarrhea
Subacute myopathy, arthralgias, headaches,
and skin rashes
Prolonged use:
Gynaecomastia, erectile dysfunction
Leucopenia and hepatic dysfunction
Vitamin B12 deficiency
Hypergastrinemia which may predispose to rebound
hypersecretion of gastric acid upon discontinuation of therapy
and may promote the growth of gastrointestinal tumors
(carcinoid tumors )
56. PPI – contd.
Drug Interaction:
Inhibits metabolism of Warfarin, Diazepam
Therapeutic uses:
1. Gastroesophageal reflux disease (GERD)
2. Peptic Ulcer - Gastric and duodenal ulcers
3. Bleeding peptic Ulcer
4. Zollinger ellison Syndrome
5. Prevention of recurrence of nonsteroidal antiinflammatory drug
(NSAID) - associated gastric ulcers in patients who continue
NSAID use.
6. Reducing the risk of duodenal ulcer recurrence associated
with H. pylori infections
7. Aspiration Pneumonia
58. Muscarinic antagonists
Atropine:
Block the M1 class receptors
Reduce acid production
Abolish gastrointestinal spasm
Pirenzepine and Telenzepine
Mechanism of action:
• Reduce meal stimulated HCl secretion by reversible blockade of
muscarinic (M1) receptors on the cell bodies of the intramural
cholinergic ganglia
(receptors on parietal cells are M3).
Unpopular as a first choice because of high incidence of
anticholinergic side effects (dry mouth and blurred vision)
59. Prostaglandin
analogues(PGE2,PGI2)
Inhibit gastric acid secretion
Exhibit ‘cytoprotective’ activity
Enhance local production of mucus or
bicarbonate(PGE2)
Promote local cell regeneration
Help to maintain mucosal blood flow
60. Prostaglandin analogues -
Misoprostol
Actions:
Inhibit histamine-stimulated gastric acid secretion
Stimulation of mucin and bicarbonate secretion
Increase mucosal blood flow
(Reinforcing of mucous layer buffered by HCO3
secretion from epithelial cells)
Therapeutic uses:
Prevent ion of NSAID-induced mucosal injury
(rarely used because it needs frequent
administration – 4 times daily)
61. Misoprostol
Doses: 200 mcg 4 times a day (Misoprost)
ADRs:
Diarrhoea and abdominal cramps
Uterine bleeding
Abortion
Exacerbations of inflammatory bowel disease and
should be avoided in patients with this disorder
Contraindications:
1. Inflammatory bowel disease
2. Pregnancy (may cause abortion)
Newer- Rioprostadil and Enprostil
62. Omeprazole
Amoxicillin
Clarithromycin
Metronidazole
Eradication of H.pylori
63. Triple Therapy
The BEST among all the Triple therapy regimen is:
Omeprazole / Lansoprazole - 20 / 30 mg bd
Clarithromycin - 500 mg bd
Amoxycillin / Metronidazole - 1gm / 500 mg bd
Given for 14 days followed by P.P.I for 4 – 6 weeks
Short regimens for 7 – 10 days not very effective
66. Colloidal Bismuth Subcitrate
Pharmacological actions:
• Undergoes rapid dissolution in the stomach into
bismuth oxychloride and citrate
• Bismuth coats ulcers and erosions protecting
them from acid and pepsin and increases
prostaglandin and bicarbonate production
• Uses:
• Part of triple regimen
• Treatment of dyspepsia and traveller’s
diarrhoea
67. NSAIDS Related Ulcer
Active Ulcer
NSAID discontinued-H2
antagonists/PPI
NSAID continued-PPI
Prophylaxis
Misoprostol/PPI
68. IR – OME(INSTANT RELEASE OMEPRAZOLE
SACHET)
IR-OME is unique among PPI formulations in that it has no
enteric coating
Peak plasma concentration within 30 min
Rapid absorption of OME and rapid onset of antisecretory effect
Single daily doses of IR-OME produce prolonged acid
suppression, including postprandial periods
Achieves intragastric pH>4 for 18.6 hours
The favorable pK and pD profiles seen with IR-OME do not
appear to be achievable by using an antacid with a DR-PPI,
because this is not associated with improvement or
acceleration of PPI absorption
69. Mechanism of action of IR – OME
NaHCO 3 buffers the acid
NaHCO 3 buffers the acid NaHCO3
In gastric lumen –– raises
In gastric lumen raises OME
Intra-gastric pH
Intra-gastric pH
Increase in gastrin
Increase in gastrin
release
release
Increased Activation of more Proton
Activation of more Proton
Gastrin pumps
pumps
secretion
With rapid absorption, most of newly
With rapid absorption, most of newly
activated Proton pumps are blocked
activated Proton pumps are blocked
Quick & prompt acid inhibition
Quick & prompt acid inhibition
70. Potential Advantages of IR – OME
• Buffer protects the PPI from acid degradation in stomach
no need for an enteric coating
absorption more rapid & predictable
• Immediate therapeutic effect due to acid buffering
•Rapid rise in pH (>6 in 1 min) may stimulate gastrin release
temporary stimulation of proton pumps - > improves
uptake of OME by parietal cells
•Independent of food intake
•More rapid & long lasting control of acid secretion
71. Conclusion
•Compared to IV H2RAs and IR – OME given by NG
tube is as effective in treating erosive gastritis.
•IR-OME provides more rapid, effective & sustained pH
control.
•IR – OME is the only PPI that is US FDA approved
for the reduction of risk of UGI bleeding.
