Treatment of Peptic Ulcer

& GERD
Dr. Dian Novita, dr., MKed.
Dept. Farmakologi & Terapi FK UKWMS
e-mail : [email protected]

Physiology of Gastric Secretion

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 Hydrochloric Acid
• Secreted by the parietal cells when stimulated by
food
• Maintains stomach at pH of 1 to 4
• Secretion also stimulated by:
• Large fatty meals
• Excessive amounts of alcohol
• Emotional stress

Protective Factors in Gastric

Mucosa
• Gastric mucus
• Prostaglandin

Prostaglandins stimulate mucus secretion

NSAIDs & anticholinergic medications inhibit mucus production

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 Acid-Related Diseases (1)
• Caused by imbalance of the three cells of
the gastric gland and their secretions
• Most common: hyperacidity
• Clients report symptoms of
overproduction of HCl by the parietal cells
as indigestion, sour stomach, heartburn,
acid stomach

Acid-Related Diseases (2)

• PUD: peptic ulcer disease
• GERD: gastroesophageal reflux disease
• Helicobacter pylori (H. pylori)
• Bacterium found in GI tract of 90% of patients with
duodenal ulcers, and 70% of those with gastric
ulcers
• Combination therapy is used most often to
eradicate H. pylori
• Primarily colonizes in the antrum of the stomach;
• Resides mainly within the gastric mucus;
• Has a high activity of the enzyme urease which
enables it to colonize in the stomach

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 What is Peptic Ulcer Disease
Definition of Peptic Ulcer:
A benign lesion of gastric or duodenal mucosa
occurring at a site where the mucosal
epithelium is exposed to acid and pepsin;

1) Excess acid production

2) Intrinsic defect in the mucosal defense
barrier

The Role of H.pylori in

Duodenal ulcer

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 Treatment for H. pylori
• H. pylori is not associated with acute perforating
ulcers
• It is suggested that factors other than the
presence of H. pylori lead to ulceration

The Role of
NSAIDs in
Peptic
ulcer

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 What is GERD?
Gastroesophageal Reflux Disease (GERD):

GERD is when acid and pepsin from the

stomach flows backward up into the
esophagus often called heartburn;

What Causes GERD?

1) Overproduction of acid/pepsin

2) Over relaxation of the Lower Esophageal

Sphincter (LES);

Complications;
if not treated - severe chest pains,
bleeding or a pre-malignant change in the
lining of the esophagus called Barrett’s
esophagus – can result in
adenocarcinoma

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 Barrett’s Esophagus
• Demarcated by histological
changes in cells lining the
❖Lower esophagus lined
esophagus.
❖by red-coloured tissue,
❖not the usual white-pink
❖colour. • Occurs in 10% of GERD
patients.

• Incidence is 1% in the
general population.

• Associated with
adenocarcinoma of the
esophagus.

Acid-Controlling
Agents

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 Acid-Controlling Agents

• Acid-Controlling Agents
• Antimuscarinic Agents
• Mucosal Protective Agents

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 Types of
Acid-Controlling Agents
• Antacids
• H2 antagonists
• Proton pump inhibitors

ANTACIDS

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 Antacids …1
❖ Weak bases that neutralize acid
❖ Also inhibit formation of pepsin
(As pepsinogen converted to pepsin at acidic pH)
❖ Type of antacids :
- Natrium bicarbonate
- Calcium carbonate
- Aluminum hydroxide
- Magnesium hydroxide
❖ Not part of Physician prescribed regimen
❖ OTC drug for symptomatic relief of dyspepsia

Antacids …2
Duration of action :
❖ 30 min when taken in empty stomach
❖ 2 hrs when taken after a meal
Side effects :
Natrium bicarbonate: systemic alkalosis, fluid
retention
Calcium carbonate: hypercalcemia, nephrolitiasis
Aluminum hydroxide: constipasion,
hypophosphatemia
Magnesium hydroxide: (osmotic) diarrhea,
hypermagnesemia
❖ In renal failure Al antacid – Aluminium toxicity &
3+

Encephalopathy
❖ In heart failure – Mg3+ should be avoid

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 Antacid …3
❖ Adsorb drugs and form insoluble complexes
that are not absorbed .

Clinical importance :
Interactions can be avoided by taking antacids
2 hrs before or after ingestion of other drugs .

Now answer this question

❖ Is it rational to combine aluminium hydroxide

and magnesium hydroxide in antacid
preparations ?

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 Answer
❖ Combination provides a relatively fast and
sustained neutralising capacity .
(Magnesium Hydroxide – Rapidly acting
Aluminium Hydroxide - Slowly acting )

❖ Combination preserves normal bowel function.

(Aluminium Hydroxide – constipation
Magnesium hydroxide – diarrhoea )

HISTAMINE (H2) RECEPTOR

ANTAGONIST

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 Histamine (H2)Receptor Antagonist
❖ Reversible competitive inhibitors of H2 receptor

❖ Highly selective, No action on H1 or H3 receptors

❖ Very effective in inhibiting nocturnal acid

secretion ( as it depends largely on Histamine )
❖ Modest impact on meal stimulated acid
secretion (As it depends on gastrin, acetyl
choline and histamine)

Cimetidine Ranitidine Famotidine Nizatidine

Bioavailability 80 50 40 >90
Relative Potency 1 5 -10 32 5 -10
Half life (hrs) 1.5 - 2.3 1.6 - 2.4 2.5 - 4 1.1 -1.6
Duration of 6 8 12 8
action (hrs)
Inhibition of 1 0.1 0 0
CYP 450
Dose mg(bd) 400 150 20 150

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 Side effects & Interactions

❖ Extremely safe drugs

❖ Cimetidine causes gynecomastia,
galactorrhea
(as it is antiandrogenic & increases prolactin level)
❖ Cimetidine inhibits CYP450 & increases
concentration of Warfarin, Theophylline,
Phenytoin, Ethanol, etc.

PROTON PUMP INHIBITORS

(PPIs)

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 Proton Pump Inhibitors (PPIs) …1
❖ Most effective drugs in antiulcer therapy

❖ Irreversible inhibitor of H+ K+ ATPase (proton pump)

❖ Prodrugs requiring activation in acid environment

❖ Weakly basic drugs & so accumulate in canaliculi of

parietal cell
❖ Activated in canaliculi & binds covalently to
extracellular domain of H+ K+ ATPase → trapping the
PPIs so that it cannot diffuse back across the
canalicular membrane
❖ Acid secretion resumes only after synthesis of new
molecules

To prevent degradation of PPIs by acid in the

gastric lumen → oral dosage forms formulations:
• enteric-coated drugs contained inside gelatin capsules
(omeprazole, dexlansoprazole, esomeprazole, and lansoprazole)
• enteric-coated granules supplied as a powder for
suspension (lansoprazole)
• enteric-coated tablets (pantoprazole, rabeprazole, and omeprazole)
• powdered omeprazole combined with sodium bicarbonate
(ZEGERID)

The delayed-release and enteric-coated tablets dissolve only at

alkaline pH, whereas admixture of omeprazole with sodium
bicarbonate simply neutralizes stomach acid; both strategies
substantially improve the oral bioavailability of these acid-labile
drugs

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 Pharmacokinetics
❖ Given as enteric coated granules in capsule or
enteric coated tablets
❖ Pantoprazole also given intravenously

❖ Half life – 1.5 hrs

❖ Since it requires acid for activation - given 30
mnts before meals
Other acid suppressing agents not co-
administered

PPIs …2
• AE : nausea, abdominal pain, constipation, flatulence,
and diarrhea. Subacute myopathy, arthralgias,
headaches, and skin rashes
• PPIs (omeprazole) metabolized by hepatic CYPs
• Drug Interaction : with warfarin (esomeprazole,
lansoprazole, omeprazole, and rabeprazole), diazepam
(esomeprazole and omeprazole), and cyclosporine
(omeprazole and rabeprazole)
• Omeprazole (long term use) decreases the absorption
of vitamin B12

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 PPIs …3
• Among the proton pump inhibitors, only omeprazole
inhibits CYP2C19 (thereby decreasing the clearance of
disulfiram, phenytoin, and other drugs) & induces the
expression of CYP1A2 (thereby increasing the clearance of
imipramine, several antipsychotic drugs, tacrine, and
theophylline)
• Omeprazole can interact adversely with the anticlotting
agent, clopidogrel (CYP2C19) → inhibit conversion of
clopidogrel to the active anticoagulating form.
• Pantoprazole is less likely to result in this interaction

Now Answer this Question

A patient comes to your clinic at midnight

complaining of heart burn. You want to relieve
his pain immediately. What drug will you
choose?

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 Answer :
Antacids

Explanation :
Antacids neutralize the already secreted acid in
the stomach. All other drugs act by stopping acid
secretion and so may not relieve symptoms at
least for 45 min.

Antimuscarinic Agents –
Acid Supressant &
Cytoprotectant

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 ANTIMUSCARINIC AGENTS
❖PIRENZEPINE
❖TELENZEPINE
❖ suppress neural stimulation of acid production
via actions on M1 receptors of intramural ganglia
❖ relatively poor efficacy, significant and
undesirable anticholinergic side effects, and risk
of blood disorders (pirenzepine), they rarely are
used today

Mucosal Protective Agents

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 Mucosal Protective Agents
❖ Sucralfate
❖ Prostaglandin Analogs: Misoprostol

❖ Colloidal Bismuth compounds

Sucralfate
❖ Salt of sucrose complexed to sulfated aluminium
hydroxide
❖ In acidic pH polymerises to viscous gel that
adheres to ulcer crater
❖ Taken on empty stomach 1 hr. before meals
❖ Concurrent antacids, H2 antagonist avoided

( as it needs acid for activation )

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 Misoprostol
❖ PGE1 analogue

❖ Modest acid inhibition

❖ Stimulate mucus & bicarbonate secretion

❖ Enhance mucusal blood flow

❖ Approved for prevention of NSAID induced
ulcer
❖ Diarrhoea & cramping abd. pain – 20 %

❖ Not so popular as P.P.I are more effective &

better tolerated

Colloidal Bismuth Compounds

❖ Coats ulcer, stimulates mucus & bicarbonate
secretion
❖ Direct antimicrobial activity against H.pylori
❖ May cause blackening of stools & tongue

❖ Not used for long periods – bismuth toxicity

Available compounds :
❖ Bismuth subsalicylate – in USA

❖ Bismuth sobcitrate – in Europe

❖ Bismuth dinitrate

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 Now answer this question

❖ A pregnant lady (first trimester) comes to you

with peptic ulcer disease. Which drug will you
prescribe for her ?

❖ Answer :

Antacids or Sucralfate

❖ Explanation ;
H2 antagonists cross placenta and are also
secreted in breast milk. Safety of Proton pump
inhibitors not established in pregnancy.
Misoprostol causes abortion .

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 ADDITIONAL DRUG FOR GERD

Dopamine Receptor
Antagonists
Metoclopramide
• M.O.A : complex & involve 5-HT4 receptor agonism,
vagal and central 5-HT3 antagonism, and possible
sensitization of muscarinic receptors on smooth muscle
• An ancient Prokinetic agents
• Effect mostly upper digestive tract: increases lower
esophageal sphincter tone & stimulates antral and small
intestinal contractions
• Produce symptomatic relief of, but not healing of,
associated esophagitis

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 Eradication of H.pylori

Triple Therapy
❖ The BEST among all the Triple therapy
regimen is

Omeprazole / Lansoprazole
Clarithromycin
Amoxycillin / Metronidazole

❖ Given for 14 days followed by P.P.I for 4 – 6 weeks

❖ Short regimens for 7 – 10 days not very effective

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 Quadruple Therapy

❖ Given when Triple Therapy fails

❖ Omeprazole / Lansoprazole
Bismuth subsalycilate
Metronidazole
Tetracycline

Now you have learnt about drugs used for treating

peptic ulcer ? Are there any drugs that can cause peptic
ulcer ?

Drugs causing peptic ulcer

➢ Non Steroidal Anti Inflammatory Drugs
(NSAIDs)
➢ Glucocorticoids

➢ Cytotoxic agents

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 ❖ Stress induced ulceration after head trauma
Cushing’s ulcer
❖ Stress induced ulceration after severe burns

Curling’s ulcer

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