MANAGEMENT OF PUD AND GERD

Question 1

What is the pathophysiology of Peptic Ulcer Disease (PUD)?

Answer 1

Peptic ulceration is traditionally considered a consequence of an imbalance between aggressive and protective factors in the upper gastrointestinal tract.

Question 2

What are the principal aggressive factors of PUD?

Answer 2

①Gastric acid and pepsin
②H. pylori infection
③NSAIDs, smoking and alcohol increase the risk of ulceration.

Question 3

H. pylori contribution to PUD;

Answer 3

①Stimulates gastrin release
②Increased acid secretion in genetically susceptible individuals.
③Causes direct damage to the mucosa.

Question 4

Eradication of H. pylori infection EFFECTS on PUD;

Answer 4

Prolongs remission from peptic
ulceration and usually with permanent cure.

Question 5

H. pylori in combination with smoking;

Answer 5

Smoking in combination with H. pylori increases the risk of ulcers but not their healing.
Alcohol delays the healing!

Question 6

The aims of treatment of peptic ulceration;

Answer 6

①RELIEVE PAIN
②HEAL THE ULCER
③PREVENT　 ULCER　 RECURRENCE
④PREVENT COMPLICATIONS
E.G PERFORATION OR GI
BLEEDING

Question 7

Drugs used in the treatment of peptic ulcers；

Answer 7

①Antacids
②Drugs that inhibit gastric acid secretion:
* H2-receptor Antagonists
　* Less effective than PPIs, used to heal DU and benign GU.
* PPIs
③Drugs that do not directly inhibit gastric acid secretion:
* Sucralfate.
④Drug combinations to eradicate H. pylori.

Question 8

Antacids MoA

Answer 8

Antacids are weak bases that neutralize stomach acid by reacting with protons in the lumen of the gut and may also stimulate the protective functions of the gastric mucosa.
Antacids reduce the recurrence rate of peptic ulcers, when regularly used in large doses.

Question 9

Antacids examples;

Answer 9

①Magnesium hydroxide; has a strong laxative effect
②Aluminum hydroxide; has a constipating action
③④Calcium carbonate and sodium bicarbonate; absorbed in gut so avoided for systemic effects. Cause BLOATING and BELCHING

Question 10

H2-receptor antagonists MoA

Answer 10

Inhibit stomach
acid production. How? H2-receptor antagonists are highly specific and selective competitive antagonists of histamine, binding to gastric parietal cell, histamine H2 receptors.

They prevent activation of adenylyl cyclase and accumulation of cAMP, which mediate acid release into the gastric lumen.

Parietal cell acid secretion induced by the secretagogues; gastrin and acetylcholine,
which act synergistically with histamine, is inhibited indirectly.

Question 11

Indications of H2 receptor antagonists;

Answer 11

They are effective in the treatment of ;
①GERD,
②peptic ulcer disease, relapse common
③Non-ulcer dyspepsia
④Prevention of stress-related gastritis in seriously ill patients.

Question 12

2. H2-receptor antagonist examples;

Answer 12

①Cimetidine
②③④ranitidine, famotidine, and nizatidine

Question 13

Proton pump inhibitors MoA

Answer 13

Are lipophilic weak bases that diffuse into the parietal cell canaliculi, where they become protonated and concentrated more than 1000-fold. There they undergo conversion to compounds that irreversibly inactivate the parietal cell H+/K+ ATPase.

Question 14

Proton pump inhibitors examples

Answer 14

①Omeprazole
②③④esomeprazole, lansoprazole, pantoprazole, and
rabeprazole

Question 15

Proton pump inhibitors　indications

Answer 15

PPIs are considered the first-line drugs for treating acid peptic disease due superior efficacy and safety profile.
①GERD
②③Peptic ulcer and treatment of
nonulcer dyspepsia and the ④Prevention of stress-related mucosal bleeding.
⑤Zollinger Ellison syndrome Tx
Relief of symptoms takes from 1 to 4 days.

Question 16

Proton pump inhibitors ADVERSE REACTIONS (not common)

Answer 16

①②③④Diarrhea, abdominal pain, and
headache
⑤Chronic treatment with proton pump inhibitors may result in hypergastrinemia
⑥May decrease the oral bioavailability of vitamin B12 and certain drugs that require acidity for their gastrointestinal absorption (eg, digoxin, ketoconazole).
⑦Increase in the risk of respiratory and enteric infections.

Question 17

Drugs used to treat acid-peptic
diseases general working principle:

Answer 17

• Reduce gastric acidity (antacids, histamine H2-receptor antagonists, and PPIs)
  *Or promote the defense of the GI mucosa (sucralfate, bismuth subsalicylate, and the prostaglandin analogue;misoprostol).

Question 18

Relevant pathophysiology GERD

Answer 18

*Gastro-oesophageal reflux disease (GORD) is the reflux of stomach content into the oesophagus, causing symptoms.

*Associated with obesity, alcohol intake and increasing age.

*Most patients with GORD secrete a normal amount of gastric acid. *Reflux occurs due to a dysfunctional lower esophageal sphincter. Allowing excessive reflux of gastric contents, containing acid and pepsin, into the oesophagus.

*Damage to the mucosal surface provokes oesophageal dysmotiliy.

Question 19

Complications of GERD include:

Answer 19

Esophagitis, peptic strictures,
dysphagia, Barrett’s esophagus and esophageal adenocarcinoma.

Question 20

Medications that worsen the symptoms of GORD:

Answer 20

Calcium channel antagonists, nitrates, theophylline, bisphosphonates
(alendronate in particular).

Steroids and non-steroidal anti-inflammatory drugs (NSAIDs)

Question 21

The aims of
treatment
of GERD

Answer 21

①Eliminate symptoms
➁Prevent the relapse of esophagitis
③Prevent the development of complications
④Heal esophagitis

Question 22

Drugs used in treatment of GERD

Answer 22

①Antacids and antacid/alginate combinations
②Drugs that inhibit gastric acid secretion:
* H2-receptor Antagonists
* PPIs
③Drugs that act on esophageal and/or gastric motility.

Question 23

Prescribing points H2
antagonists

Answer 23

Reduced acid secretion by the parietal cells, especially at night and in the fasting state.
They are less effective in reducing food-stimulated acid secretion.

Question 24

Pharmacokinetics Histamine H2-receptor antagonists

Answer 24

All histamine H2-receptor antagonists can be given orally.

They are absorbed rapidly; however, cimetidine, ranitidine, and famotidine only have 50% bioavailability.

Relatively short half-lives

They are excreted largely unchanged by the kidneys.

∴ Cimetidine, famotidine, and ranitidine are available for parenteral use.

Clearance of Histamine H2-receptor antagonists, reduced in the elderly, renal and hepatic dysfunction.

Cimetidine inhibits the activity of several hepatic cytochrome P450 enzymes that can prolong the duration of action of a number of other drugs.

Question 25

H2-receptor antagonists Adverse effects

Answer 25

①Cimetidine is weakly anti-androgenic
in humans and may cause impotence
or gynaecomastia.

②Cimetidine and ranitidine may cause
reversible mental confusion,
particularly in frail, elderly patients.

③Cardiac dysrhythmias following
intravenous injections of H2-receptor
antagonists.

Question 26

Pharmacokinetics
of PPIs

Answer 26

Bioavailability is decreased by food

PPIs are best administered within an hour of meals, since maximal inhibition of H+/K +-ATPase occurs when proton pumps are actively secreting acid.

After dissolution of the enteric-coated PPI capsule in the intestine, the lipophilic prodrug diffuses into the acidic environment of the parietal cell, where it becomes protonated and highly concentrated.

It is then converted to a reactive sulfenamide cation that irreversibly binds to and inactivates parietal cell H+/K+-ATPase

Although their serum half-life is short (2–4 hours), PPI inhibition of the proton pump lasts up to 24 hours while synthesis of new H+/K+-ATPase occurs.

PPIs are metabolized by hepatic P450 microsomal enzymes; however, no
clinically significant drug-drug interactions have been documented.

Question 27

Promoters of GI mucosa defense:

Answer 27

Sucralfate
Misoprostol
Bismuth subsalicylate

Question 28

Sucralfate use replaced by other agents for the treatment of
upper GI disorders. What is it used for clinically?

Answer 28

Still used clinically to treat stress-related gastritis.
Sucralfate is a complex salt of sucrose sulfate and aluminum
hydroxide

Question 29

Mechanism of Action of Sucralfate:

Answer 29

in its viscous form may bind to positively charged proteins to
coat epithelial cells and form a physical barrier in the GI tract. That protects the luminal surface and any already formed ulcers from the effects of gastric acid and pepsin.
 Sucralfate can be given orally.
 Sucralfate is very insoluble; hence, it acts locally with little
systemic absorption from the GI tract.

Question 30

Misoprostol use

Answer 30

Misoprostol is used to treat nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcer
disease.
* Misoprostol is a prostaglandin analog of prostaglandin E1 (PGE1).

Question 31

Mechanism of Action of Misoprostol

Answer 31

Stimulates bicarbonate, mucus secretion and mucosal blood flow, resulting in enhanced
neutralization and protection from secreted acid.
Binds to parietal cell prostaglandin receptors to modestly inhibit secretagogue-induced acid
secretion.
Misoprostol is absorbed rapidly and metabolized to an active agent that has a very short serum
half-life and short duration of action. Therefore, it is administered three to four times daily.

Question 32

Bismuth subsalicylate (Pepto-Bismol) is used to treat:

Answer 32

I. Dyspepsia
II. Acute diarrhea
III. Second-line agent in a multidrug combination, H. pylori infection (quadruple
therapy).
 It is thought to inhibit growth of the organism.

Question 33

Bismuth subsalicylate MoA

Answer 33

I. Bismuth subsalicylate, coats epithelial cells to form a physical barrier in the GI
tract and protect it from the deleterious effects of gastric acid and pepsin.
II. May also stimulate bicarbonate and PGE2 secretion.
 Bismuth subsalicylate is rapidly dissociated in the stomach into bismuth, which is
eliminated in the stool, and salicylate; which is absorbed systemically.

Question 34

PPIs in triple therapy against H. Pylori

Answer 34

①Includes antibiotics clarithromycin or amoxicillin and
metronidazole. (Triple therapy)
②Bismuth subsalicylate plus thrapple therapy = quadruple therapy
③Omeprazole available orally
④PPIs pantoprazole and esomeprazole (pediatrics) are
available for parenteral use.

Question 35

Drugs
acting on
esophageal and/ or
gastric
motility

Answer 35

Metoclopramide and domperidone

Question 36

Metoclopramide and domperidone

Answer 36

They may have some efficacy in patients with mild grades of
GORD because of their actions on the motility of the upper gut:
they have a weak tonic effect on the lower esophageal sphincter;

They improve esophageal clearance and gastric emptying.

They are seldom effective alone and are used as an adjunct to
acid suppressant treatment.

Metoclopramide is not recommended for long-term use because of
its adverse effects on the central nervous system (CNS).