GASTRO INTESTINAL TRACT

ACID PEPTIC DISEASE

Dr. Win Win May

IMS, MSU (Shah Alam)

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 Acid-peptic diseases

 gastroesophageal reflux,
 Peptic ulcer (gastric and duodenal), and
 stress-related mucosal injury

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 Causes
aggressive factors (acid, pepsin,bile) overwhelm
the
defensive factors of the gastrointestinal

mucosa (mucus and bicarbonate secretion,
prostaglandins,blood flow, and the processes of
restitution and regeneration after cellular injury).
Over 90% of peptic ulcers are caused

By infection with the bacterium Helicobacter
pylori or

by use of nonsteroidal anti-inflammatory drugs
(NSAIDs).
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 Pathophysiology
 Gastrin (antral G cells into blood) or ACh (post
ganglionic PS) bind to parietal cell receptors-----
↑ cytosolic Ca++ ------ stimulates protein
kinases that stimulate acid secretion from a
H+,K+ATPase (the proton pump) on the
canalicular surface
 Gastrin upon acid secretion is mediated
indirectly through the release of histamine from
ECL cells
 acetylcholine provides potent direct parietal cell
stimulation.
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 DRUGS USED IN PU
(1) Agents that reduce intragastric acidity
 Acidity - antacid
 Volume – block the GA secretory receptors

(2) Agents that promote mucosal defense.

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 TO REDUCE GASTRIC ACIDITY
ANTACIDS
 Antacids are weak bases that react with gastric
hydrochloric acid to form a salt and water.
 Their principal mechanism of action is reduction
of intragastric acidity.
Mainstay of treatment for acid-peptic disorders
until the advent of H2 RB & PPI
 Continue used as nonprescription remedies for
the treatment of intermittent heartburn and
dyspepsia.
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 ANTACIDS
 Sodium bicarbonate(eg, baking soda, Alka
Seltzer)
 Calcium carbonate(eg, Tums, Os-Cal)
 Magnesium hydroxide or Aluminum hydroxide

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 Antacid

NaHCO3 + HCL

CaCO3 + HCL


Mg(OH)2/ Al2(OH)3 + HCL

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 AE
 Belching, abdominal distension
 Metabolic alkalosis
 Diarrhoea
 Constipation with Al compound
 Hyper Ca'mia, renal insufficiency
 milk-alkali $ with calcium containing dairy
products

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 Antacid - DI
 Antacid + drug – decreased absorption

 Tetracycline, Fluoro quinolone, Iron,

Itraconazole

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 H2RB
Chemistry & Pharmacokinetics
 Four H2 antagonists are in clinical use:
cimetidine, ranitidine, famotidine, and nizatidine.
All four agents are rapidly absorbed from the
intestine.Apart from Nizatidine the rest undergo
first-pass hepatic metabolism resulting in a
bioavailability of approximately 50%.
 The serum half-lives of the four agents range
from 1.1 to 4 hours; however, duration of action
depends on the dose given.
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 H2 RB
 Can cross the placenta & secreted into breast
milk
 cleared by a combination of hepatic
metabolism, glomerular filtration, and renal
tubular secretion.

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 Pharmacodynamic
 exhibit competitive inhibition at the parietal cell
H2receptor and suppress basal and meal-
stimulated acid secretion.
 histamine released from ECL cells by gastrin or
vagal stimulation is blocked from binding to the
parietal cell H2 receptor.
Second, direct stimulation of the parietal cell by
gastrin or acetylcholine has a diminished effect
on acid secretion in the presence of H2-RB
 Not only volume but also concentration of
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pepsin are also reduced.
 H2RB

H2antagonists are especially effective at
inhibiting nocturnal acid secretion (which
depends largely on histamine)
 Over-the counter preparations are heavily used
by the public.

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 H2RB- Clinical uses
(A) Gastroesophageal Reflux Disease (GERD)
 Patients with infrequent heartburn or dyspepsia
(fewer than 3 times per week) may take either
antacids or intermittent H2antagonists.
(B) Peptic Ulcer Disease
 Proton pump inhibitors have largely replaced
H2antagonists in the treatment of acute peptic
ulcer disease.
 Nocturnal acid suppression
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 H2RB- Clinical uses
(C) Nonulcer Dyspepsia
(D) Prevention of Bleeding from Stress-Related
Gastritis
Although most critically ill patients have normal or
decreased acid secretion, numerous studies
have shown that agents that increase
intragastric pH (H2antagonists or proton pump
inhibitors) reduce the incidence of clinically
significant bleeding.

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 H2RB-Adverse effect
 Mental status changes (confusion,
hallucinations, agitation) with IV route,
 especially in patients in the intensive care unit
who are elderly or who have renal or hepatic
dysfunction. (more common with cimetidine)
 Rapid intravenous infusion may cause
bradycardia and hypotension

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 H2RB-Adverse effect
 Cimetidine inhibits binding of
dihydrotestosterone to androgen receptors,
inhibits metabolism of estradiol, and increases
serum prolactin levels.
 long-term or in high doses, it may cause
gynecomastia or impotence in men and
galactorrhea in women. These effects are
specific to cimetidine and do not occur with the
other H2antagonists.

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 Drug Interaction
 CYP 450 enz inhibitor
 compete with creatinine and certain drugs
(eg, procainamide) for renal tubular secretion.

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 Proton Pump Inhibitors
Five proton pump inhibitors are available for
clinical use:
 omeprazole,
 lansoprazole,
 rabeprazole,
 pantoprazole,and
 esomeprazole.

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 PPI
 resemble H2 antagonists in structure but have
a completely different mechanism of action.
 All are available in oral formulations.
 Prodrug, oral products are formulated for
delayed release as acid-resistant, enteric-
coated capsules or tablets.
 Esomeprazole and pantoprazole are also
available in intravenous formulations

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 PPI
 lipophilic weak bases (pKa 4–5) and after
intestinal absorption diffuse readily across lipid
membranes into acidified compartments (eg,
the parietal cell canaliculus) ---active form,
 reactive thiophilic sulfenamide cation, which
forms a covalent disulfide bond with the H+,K+
ATPase, irreversibly inactivating the enzyme.

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 PPI -PK

The bioavailability of all agents is decreased
approximately 50% by food;

hence, the drugs should be administered on an
empty stomach.

short serum half-life of about 1.5 hours, but acid
inhibition lasts up to 24 hours owing to the
irreversible inactivation of the proton pump.

rapid first-pass and systemic hepatic
metabolism and have negligible renal clearance.
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 PPI
 proton pump inhibitors are ideal drugs: they
have a short serum half-life, they are
concentrated and activated near their site of
action, and they have a long duration of action.
 In standard doses, proton pump inhibitors
inhibit 90–98% of 24-hour acid secretion

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 PPI -PD
 Inhibit both fasting and meal-stimulated
secretion because they block the final common
pathway of acid secretion,

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 Clinical uses
1. GERD
2. PU
H-pylori associated, NSAIDs associated &Prevention
of rebleeding from peptic ulcers
3. Nonulcer Dyspepsia
4. Prevention of Stress-Related Mucosal
Bleeding
5. Gastrinoma and other Hypersecretory
conditions
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 PPI- Adverse Effects
 Safe drug
 safety during pregnancy has not been
established.
(Acid also promotes absorption of food-bound
minerals (iron, calcium, zinc) – bone?
Acid is important in releasing vitamin B12 from
food. A minor reduction in oral cyanocobalamin
absorption) – anaemia?

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 PPI - AE

Increases in gastric bacterial concentrations

Hospitalized patients may have an increased
risk for Clostridium difficileinfection.
****hyperplasia of ECLcells in response to
hypergastrinemia, carcinoid tumor formation has
not been documented.

increased gastric inflammation may accelerate
gastric gland atrophy (atrophic gastritis) and
intestinal metaplasia—known risk factors for
gastric adenocarcinoma
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 DI
 intragastric acidity affects drug bioavailability
E.g., ketoconazole, itraconazole, digoxin, and
atazanavir

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MUCOSAL PROTECTIVE AGENTS
 Mucosal prostaglandins appear to be important
in stimulating mucus and bicarbonate secretion
and mucosal blood flow.

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 SUCRALFATE

 salt of sucrose complexed to sulfated aluminum

hydroxide.
 In water or acidic solutions it forms a viscous,
tenacious paste that binds selectively to ulcers
or erosions for up to 6 hours.

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 SUCRALFATE
 negatively charged sucrose sulfate binds to
positively charged proteins in the base of ulcers
or erosion, forming a physical barrier that
restricts further caustic damage and stimulates
mucosal prostaglandin and bicarbonate
secretion.

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 Clinical Uses
 Sucralfate reduces the incidence of clinically
significant upper gastrointestinal bleeding in
critically ill patients hospitalized in the intensive
care unit, although it is slightly less effective
than intravenous H2antagonists
 prevention of stress related bleeding

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 Adverse effects & DI
 Less systemic SE because it is not absorbed
 should not be used for prolonged periods
in patients with renal insufficiency, (small amount
of Al++ is absorbed)

 Sucralfate & antacid/H2RB?

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 PROSTAGLANDIN ANALOGS
Misoprostol (PG E1)
After oral administration, it is rapidly absorbed
and metabolized to a metabolically active free
acid. The serum half-life is less than 30minutes;
hence, it must be administered 3–4 times daily.
It is excreted in the urine; however, dose
reduction is not needed in patients with renal
insufficiency

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 PG E1

both acid inhibitory and mucosal protective
properties.

stimulate mucus and bicarbonate secretion and
enhance mucosal blood flow. In addition, it
binds to a prostaglandin receptor on parietal
cells, reducing histamine-stimulated cAMP
production and causing modest acid inhibition.

stimulation of intestinal electrolyte and fluid
secretion, intestinal motility, and uterine
contractions
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 Clinical uses
 Misoprostol reduces the incidence of NSAID-
induced ulcers to less than 3% and
 the incidence of ulcer complications by 50%.

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 Adverse Effects & Drug Interactions
Diarrhea and cramping abdominal pain occur in
10–20% of patients. Because misoprostol
stimulates uterine contractions, it should not be
used during pregnancy or in women of
childbearing potential unless they have a
negative serum pregnancy test and are
compliant with effective contraceptive
measures.
 No significant drug interactions are reported.

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 BISMUTH COMPOUNDS
Chemistry & Pharmacokinetics
 Two bismuth compounds are available: bismuth
subsalicylate,a nonprescription formulation
containing bismuth and salicylate, and
 bismuth subcitrate potassium

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 PD
 Bismuth coats ulcers and erosions, creating a
protective layer against acid and pepsin.
 also stimulate prostaglandin, mucus, and
bicarbonate secretion.
 Bismuth subsalicylate reduces stool frequency
and liquidity in acute infectious diarrhea, due to
salicylate inhibition of intestinal prostaglandin
and chloride secretion.

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 PD
 has direct antimicrobial effects and binds
enterotoxins, accounting for its benefit in
preventing and treating traveler’s diarrhea.
 Has direct antimicrobial activity against H
pylori.

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 Clinical uses
 dyspepsia and acute diarrhea.
 Bismuth subsalicylate also is used for the
prevention of traveler’s diarrhea (30 mL or 2
tablets four times daily)
 4 drug regimens for the eradication of H pylori
infection. PPI twice daily + bismuth
subsalicylate (2 tablets; 262 mg each)+
tetracycline (250–500 mg), +metronidazole (500
mg) four times daily for 10–14 days

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 Adverse effects
 harmless blackening of the stool, Liquid
formulations may cause harmless darkening of
the tongue
 should be used for short periods only and
should be avoided in patients with renal
insufficiency.

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 AE
 Prolonged usage of some bismuth compounds
may rarely lead to bismuth toxicity, resulting in
encephalopathy (ataxia, headaches, confusion,
seizures). However, such toxicity is not reported
with bismuth subsalicylate or bismuth citrate.
 High dosages of bismuth subsalicylate may
lead to salicylate toxicity.

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 Antimicrobial agents
To erradicate H.pylori infection
 Amoxycillin
 Tetracycline
 Clarithromycin
 Metronidazole

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 standard “triple therapy” regimens
1st line therapy

 proton pump inhibitor,

 clarithromycin, and
 amoxicillin or metronidazole twice daily for 14
days)

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 4drugs regimen
 2nd line therapy
 PPI twice daily combined with three capsules of
a combination prescription formulation (each
capsule containing bismuth subcitrate 140 mg,
metronidazole 125 mg, and tetracycline 125
mg) taken four times daily for 10 days

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 THANK YOU

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