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Drugs for Peptic Ulcer Disease Basheerahmed AM What is peptic ulcer?Substitution of antibiotics (that is, do not substitute "ampicillin for amoxicillin" or "doxycycline for tetracycline"). Recommended duration of therapy 10 - 14 days

H2-Receptor Antagonists The receptor-mediated binding of acetylcholine, histamine, or gastrin results in the activation of protein kinases. The kinases stimulate the proton pumps to secrete hydrogen ions in exchange for K+ into the lumen of the stomach. These agents reduce the secretion of gastric acid by competitively blocking the binding of histamine to H2 receptors. Thy inhibit ? basal, ? food-stimulated, and ? nocturnal secretion of gastric acid by about 90%. Cimetidine, the first histamine H2-receptor antagonist, is rarely used due to a wide range of drug- drug interactions. o o Therapeutic Uses Peptic Ulcers: All agents are equally effective in promoting healing. If H. pylori infection is present, use in combination with antibiotics. PPIs are more effective in treating NSAID-induced ulcers. Selectivity of H2-receptor antagonists No effect on H1 receptors Selective for H2 receptors Therapeutic Uses Acute stress ulcers can develop in patients admitted to intensive care units, such as, critically ill surgical patients, or patients with sepsis, respiratory failure etc. Some of these patients may be unconscious. Intravenous drugs are administered to manage stress ulcers. PPIs are more effective because tolerance may develop to H2 receptor antagonists. Gastroesophageal Reflux Disease (GERD) Low-dose H2 receptor antagonists are effective for GERD in only 50% of patients. Onset of action: 45 minutes, therefore, antacids relieve heartburn more quickly. PPIs are preferred ? ? ? Pharmacokinetics Route of Administration: Oral, IV Absorption and Distribution: Well absorbed orally and distributed widely throughout the body: Use in pregnancy: Available data shows no increased risk of congenital malformations, or low infant birth weight: Excretion: urine Intravenous formulations: Cimetidine Ranitidine Famotidine. Half-life: Increased in patients with renal dysfunction, and dosage adjustments are needed. ? ? Adverse Effects In general, the H2 antagonists are well tolerated. Cimetidine is a nonsteroidal antiandrogen. It can produce the following effects Gynecomastia and Galactorrhea (discharge of milk). The other agents do not produce the antiandrogenic and prolactin-stimulating effects of cimetidine. Elderly patients may experience confusion after IV administration. ? ? ? Adverse Effects Cimetidine can interfere with the metabolism of Warfarin Phenytoin Clopidogrel All H2 receptor antagonists may reduce the efficacy of drugs that require an acidic environment for absorption, such as ketoconazole. Cimetidine inhibits several cytochrome P450 isoenzymes

Proton Pump Inhibitors (Inhibitors of H+/K+-ATPase - "The hydrogen/potassium pump" also called "The Proton Pump") IN Flow won't stop if you shut any one of the inlets IN But if you block the outlet, there will be no flow THE FINAL COMMON PATHWAY CLOSED IN IN OU T Actions of PPIs PPIs are prodrugs with an acid-resistant enteric coating to prevent them from premature activation by gastric acid.It forms a stable "covalent" bond with H+/K+ ATPase. The proton pump is permanently inactivated. PPIs are weak bases

At therapeutic doses, PPIs inhibit both basal and mealtime acid secretion by more than 90% (please note these patients have hyperacidity, they still have enough acid to activate pepsin during meals). PPIs need an hour for onset of acid suppression. For faster action, an oral preparation containing omeprazole and sodium bicarbonate is available in the market. Pharmacokinetics All of these agents are effective orally. For maximum effect, PPIs should be taken 30 to 60 minutes before breakfast or the largest meal of the day. Although the plasma half-life of these agents is only a few hours, they have a long duration of action due to covalent bonding with the H+/K+- ATPase enzyme. Excretion: Metabolites of these agents are excreted in urine and feces. Dexlansoprazole has a dual delayed release formulation and can be taken without regard to food. Dual release multi- particulates IV formulations ? Esomeprazole ? Pantoprazole ? Lansoprazole are also available in intravenous formulations. Adverse Effects of PPIs (Clopidogrel is an antiplatelet drug) Because clopidogrel is a prodrug. it is converted to active form by CYP-2C19. PPIs inhibit this enzyme. Vitamin B12 deficiency: Because an acidic environment is required for "B12 and intrinsic factor" complex formation Absorption of calcium carbonate decreases.H. pylori Infection H. pylori are invariably found in ulcer craters 50% of world population is infected with H. pylori

What Causes Peptic Ulcer Disease o Helicobacter Pylori (H. pylori)

• Most ulcers are the result of infection with H. pylori
• Not all of those infected with H. pylori develop ulcers
• H. pylori MAY result in a weakening of the mucosal defense systems, allowing for development of ulcer subsequent to acid/pepsin aggression; 3/24/2022 13 Role of H. pylori in Peptic Ulcer Disease o Diagnosis:
• The majority cases of peptic ulcer disease are related to H. pylori.- The diagnosis of H. pylori infection must be confirmed prior to initiation of therapy (histology and culture)
• Urea breath test 3/24/2022 14 Figure 28.2 (still) 3/24/2022 15 Chapter 28 MENU > Urease Urease Urease Urease Urease Urease Urea H2O Urease Urease Urease Urease Urease Ammonia cloud Urease Urease 3/24/2022 Urease Urease Urease Urease Type IV secretion system 16 Urease Urease Urease NH3 2CO 2

NH3 cloud is formed by the action of urease enzyme H. pylori produces large amounts of the enzyme urease, molecules of which are localized inside and outside of the bacterium.Pathogenesis o In normal acid/pepsin attack is balanced by mucosal defences o Increased attack by hyperacidity o Weakened mucosal defence - the major factor (H. pylori related) 3/24/2022 5 o o What Causes Peptic Ulcer Disease o NonSteroidal AntiInflammatory Drugs (NSAIDs) Long term use of nonsteroidal anti-inflammatory drugs.o It is defined as mucosal erosions equal to or greater than 0.5 cm. o As many as 70-90% of such ulcers are associated with Helicobacter pylori, a rod-shaped bacterium that lives in the 3/24/2022 2 Gram negative bacterium Figure 28.3 (still) 3/24/2022 3 Chapter 28 MENU > o The two main causes of peptic ulcer disease are infection with gram-negative Helicobacter pylori and the use of nonsteroidal anti- inflammatory drugs (NSAIDs).Mucosal Protective Agents Bismuth subsalicylate Brief Review of Pathophysiology

Components involved in providing gastroduodenal mucosal defense and repair HCO3 HCO3 HCO3 HCO3 3/24/2022 9 If patients are unable to tolerate the above therapies, neutralizing gastric acid with nonabsorbable antacids is an option.Bismuth compounds ????2.3.4.1.2.3.2.3.4.1.??2.

Drugs for Peptic Ulcer Disease Basheerahmed AM
What is peptic ulcer?
• A peptic ulcer, also known as peptic ulcer disease (PUD), is the most common ulcer of an area of the GIT that is usually acidic and thus extremely painful.
• It is defined as mucosal erosions equal to or greater than 0.5 cm.
• As many as 70–90% of such ulcers are associated with Helicobacter pylori, a
rod-shaped bacterium that lives in the
3/24/2022 2
Gram negative bacterium
Figure 28.3 (still)
3/24/2022 3
Chapter 28 MENU >
• The two main causes of peptic ulcer disease are infection with gram-negative Helicobacter pylori and the use of nonsteroidal anti- inflammatory drugs (NSAIDs).
• Increased hydrochloric acid (HCl) secretion and inadequate mucosal defense against gastric acid also play a role.

Pathogenesis

• In normal acid/pepsin attack is balanced by mucosal defences
• Increased attack by hyperacidity
• Weakened mucosal defence – the major factor (H. pylori related)
3/24/2022 5
•
•
What Causes Peptic Ulcer Disease
• NonSteroidal AntiInflammatory Drugs (NSAIDs) Long term use of nonsteroidal anti-inflammatory
drugs. NSAIDs block COX enzymes and decrease prostaglandins (PGs).
Gastrinoma (Zollinger-Ellison Syndrome) Tumors of the duodenum or pancreas and
secrete abnormally high amounts of gastrin which stimulates gastric acid.
Stress ulcers
Result of physical trauma
3/24/2022 6
Drug List
Drugs for Peptic Ulcer Disease and Gastroesophageal Reflux Disease (GERD)
Antimicrobial Drugs
H2-Histamine
Receptor Blockers
Proton Pump Inhibitors (PPIs)
Prostaglandin Analogue
● Amoxicillin
● Clarithromyc
in
● Metronidazo
le
● Tetracyclin
● Bismuth
compounds
● ● ● ●
ne e e ne
Famotidi Ranitidin Nizatidin Cimetidi
● Omeprazole
● Esomeprazole
● Pantoprazole
● Rabeprazole
● Lansoprazole
● Dexlansopraz
ole
●
Misoprost (a synthetic
prostaglandi n E1 [PGE1])
ol
●
Anti-muscarinic Agent
Dicyclomine
●
Antacids
Aluminum Hydroxide
●
Mucosal Protective Agents
Bismuth subsalicylate
Brief Review of Pathophysiology

Components involved in providing gastroduodenal mucosal defense and repair
HCO3 HCO3 HCO3 HCO3
3/24/2022
9
If patients are unable to tolerate the above therapies, neutralizing gastric acid with nonabsorbable antacids is an option.
H. pylori Infection
H. pylori are invariably found in ulcer craters 50% of world population is infected with
H. pylori

What Causes Peptic Ulcer Disease
• Helicobacter Pylori (H. pylori)
– Most ulcers are the result of infection with H.
pylori
– Not all of those infected with H. pylori develop ulcers
– H. pylori MAY result in a weakening of the mucosal defense systems, allowing for development of ulcer subsequent to acid/pepsin aggression;
3/24/2022 13
Role of H. pylori in Peptic Ulcer Disease
• Diagnosis:
– The majority cases of peptic ulcer disease
are related to H. pylori.
– The diagnosis of H. pylori infection must be
confirmed prior to initiation of therapy
(histology and culture)
– Urea breath test
3/24/2022
14
Figure 28.2 (still)
3/24/2022 15
Chapter 28 MENU >
Urease
Urease
Urease
Urease Urease Urease
Urea H2O
Urease
Urease Urease Urease
Urease
Ammonia cloud
Urease
Urease
3/24/2022
Urease
Urease Urease Urease
Type IV secretion system
16
Urease
Urease Urease
NH3 2CO 2

NH3 cloud is formed by the action of urease enzyme
H. pylori produces large amounts of the enzyme urease, molecules of which are localized inside and outside of the bacterium. Urease breaks down urea (which is normally secreted into the stomach) to carbon dioxide and ammonia (which neutralizes gastric acid).
The survival of H. pylori in the acidic stomach is dependent on urease, and it would eventually die without the enzyme.
The ammonia that is produced is toxic to the epithelial cells, and, along with the other products of H. pylori—including protease, vacuolating cytotoxin A (VacA), and certain phospholipases—damages those cells.
Thus
1.
2.
3. 4.
H. pylori penetrate the mucus layer of host stomach and adhere the surface of gastric mucosal epithelial cells.
produce ammonia from urea by the urease, and the ammonia netralize the gastric acid to escape from elimination.
prolifirate, migrate, and finally form the infectious focus.
The gastric ulcerization is developed by destruction of mucosa, inflammation and mucosal cell death.
3/24/2022 18
Helicobacter Pylori
The bacterium causing peptic ulcer disease
i.e., the antrum.
H. Pylori infects the lower part of the stomach,
Antimicrobial Agents
ACG guidelines recommend that all patients with a positive test of active infection with H. pylori should be offered antimicrobial treatment.
Who should be tested for H. pylori infection?
Patients with duodenal or gastric ulcers (but not patients with GERD).
Eradication of H. pylori results in rapid healing of active ulcers and less than 15% recurrence rates.
With acid reducing therapy alone, the recurrence rates are 60% to 100% per year.

Triple Therapy Treatment of First Choice
A PPI (proton pump inhibitor). Amoxicillin (metronidazole may be used in
penicillin-allergic patients). Clarithromycin.
CAUTI ON
Before prescribing antibiotics:
Obtain history of previous exposure to antibiotics.
Prescribe clarithromycin in areas where resistance is lower than 15 %.
Recommended duration of therapy = 14 days

● ●
2.
Quadruple Therapy Treatment of First Choice
Quadruple therapy should be considered in areas with high resistance to clarithromycin (> 15%).
Bismuth subsalicylate Metronidazole
Tetracycline
A PPI (proton pump inhibitor).
Eradication of H. pylori is greater than 90% with
both therapies. Not recommended
Treatment with a single antimicrobial
It is much less effective
It results in antimicrobial resistance.
Substitution of antibiotics (that is, do not substitute “ampicillin for amoxicillin” or “doxycycline for tetracycline”).
Recommended duration of therapy 10 – 14 days

H2-Receptor Antagonists
The receptor-mediated binding of acetylcholine, histamine, or gastrin results in the activation of protein kinases.
The kinases stimulate the proton pumps to
secrete hydrogen ions in exchange for K+ into the lumen of the stomach.
These agents reduce the secretion of gastric acid by
competitively blocking the binding of histamine to H2
receptors.
Thy inhibit ☛ basal, ☛ food-stimulated, and ☛ nocturnal secretion of gastric acid by about 90%.
Cimetidine, the first histamine H2-receptor antagonist, is rarely used due to a wide range of drug– drug interactions.
• •
Therapeutic Uses Peptic Ulcers:
All agents are equally effective in promoting healing.
If H. pylori infection is present, use in combination with antibiotics.
PPIs are more effective in treating NSAID-induced ulcers. Selectivity of H2-receptor antagonists
No effect on H1 receptors Selective for H2 receptors
Therapeutic Uses
Acute stress ulcers can develop in patients admitted to intensive care units, such as, critically ill surgical patients, or patients with sepsis, respiratory failure etc.
Some of these patients may be unconscious.
Intravenous drugs are administered to manage stress ulcers.
PPIs are more effective because tolerance
may develop to H2 receptor antagonists.
Gastroesophageal Reflux Disease (GERD)
Low-dose H2 receptor antagonists are effective for GERD in only 50% of patients.
Onset of action: 45 minutes, therefore, antacids relieve heartburn more quickly.
PPIs are preferred
● ● ●
Pharmacokinetics Route of Administration: Oral, IV
Absorption and Distribution: Well absorbed orally and distributed widely throughout the body:
Use in pregnancy: Available data shows no increased risk of congenital malformations, or low infant birth weight:
Excretion: urine Intravenous formulations:
Cimetidine Ranitidine Famotidine.
Half-life: Increased in patients with renal dysfunction, and dosage adjustments are needed.

● ●
Adverse Effects
In general, the H2 antagonists are well tolerated. Cimetidine is a nonsteroidal antiandrogen.
It can produce the following effects
Gynecomastia and
Galactorrhea (discharge of milk).
The other agents do not produce the antiandrogenic and prolactin-stimulating effects of cimetidine.
Elderly patients may experience confusion after IV administration.
● ● ●
Adverse Effects
Cimetidine can interfere with the metabolism of Warfarin
Phenytoin Clopidogrel
All H2 receptor antagonists may reduce the efficacy
of drugs that require an acidic environment for absorption, such as ketoconazole.
Cimetidine inhibits several cytochrome P450 isoenzymes

Proton Pump Inhibitors
(Inhibitors of H+/K+-ATPase - “The hydrogen/potassium pump” also called “The Proton Pump”)
IN
Flow won’t stop if you shut any one of the inlets
IN
But if you block the outlet, there will be no flow
THE FINAL COMMON PATHWAY CLOSED
IN
IN
OU T
Actions of PPIs
PPIs are prodrugs with an acid-resistant enteric coating to prevent them from premature activation by gastric acid.
The coating is removed in alkaline medium of the
duodenum.
PPIs are absorbed and transported via blood stream to the parietal cells.
In the acidic milieu just outside the parietal cell, the PPIs are converted to active drug by gaining an H+.
It forms a stable “covalent” bond with H+/K+ ATPase.
The proton pump is permanently inactivated.
PPIs are weak bases

At therapeutic doses, PPIs inhibit both basal and mealtime acid secretion by more than 90% (please note these patients have hyperacidity, they still have enough acid to activate pepsin during meals).
PPIs need an hour for onset of acid suppression.
For faster action, an oral preparation containing omeprazole and sodium bicarbonate is available in the market.
Pharmacokinetics
All of these agents are effective orally.
For maximum effect, PPIs should be taken 30 to 60 minutes before breakfast or the largest meal of the day.
Although the plasma half-life of these agents is only a few hours, they have a long duration of action due to covalent
bonding with the H+/K+- ATPase enzyme.
Excretion: Metabolites of these agents are excreted in urine and feces.
Dexlansoprazole has a dual delayed release formulation and can be taken without regard to food.
Dual release multi- particulates
IV formulations
● Esomeprazole ● Pantoprazole ● Lansoprazole
are also available in intravenous formulations.

Adverse Effects of PPIs
(Clopidogrel is an antiplatelet drug) Because clopidogrel is a prodrug. it is converted to active
form by CYP-2C19. PPIs inhibit this enzyme. Vitamin B12 deficiency:
Because an acidic environment is required for “B12 and intrinsic factor” complex formation
Absorption of calcium carbonate decreases. Use “calcium citrate” instead.
Diarrhea is an adverse effect of PPIs. Discontinue drug and consult physician if diarrhea persists for many days.
Prostaglandins Prostaglandins have a cytoprotective effect:
Prostaglandin E, produced by the gastric mucosa, inhibits secretion of acid and stimulates secretion of mucus and bicarbonate.
A deficiency of prostaglandins is thought to be involved in the pathogenesis of peptic ulcers.
Misoprostol [mye-soe-PROSTole], an analog of prostaglandin E1, is approved for the prevention of NSAID-induced gastric ulcers.
However, PPIs are preferred agents for the prevention of NSAID-induced ulcers.
Prophylactic use of misoprostol should be considered in patients who are taking NSAIDs and are at moderate to high risk of NSAID-induced ulcers, such as elderly patients and those with previous ulcers.
Contraindication - Pregnancy
Misoprostol can stimulate . uterine contractions and
cause miscarriage.
Dose-related
diarrhea and nausea are the most common adverse effects and limit the use of this agent.
Antacids

● ● ●
Antacids are weak bases that react with gastric acid to form water and a salt to diminish gastric acidity.
Because pepsin (a proteolytic enzyme) is inactived at a pH greater than 4, antacids reduce pepsin activity.
Antacid products vary widely in their Acid-neutralizing capacity Sodium content
Palatability, and price.

● ● ●
The efficacy of an antacid depends on
Its capacity to neutralize gastric HCl.
Whether the stomach is full or empty (food delays stomach emptying allowing more time for the antacid to react).
Commonly used antacids are
Aluminum hydroxide Magnesium hydroxide. Calcium carbonate
Calcium carbonate [CaCO3] reacts with HCl to form CO2 (may cause bloating and distention).
Systemic absorption of sodium bicarbonate [NaHCO3] can produce transient metabolic alkalosis.
Therefore, this antacid is not recommended for long- term use.
● ● ●
Therapeutic Uses
Symptomatic relief of peptic ulcer disease and GERD
For promoting healing of duodenal ulcers.
Calcium carbonate preparations are also used as calcium supplements for the treatment of osteoporosis.
They should be administered after meals for maximum effectiveness.
CAUTION: Antacids form non-absorbable complexes with many drugs. All drugs should be taken either 2 hours before or 2 hours after ingesting antacids.

● ●
Adverse Effects Aluminum hydroxide causes constipation. Magnesium hydroxide causes diarrhea.
Is absorption of the cations from antacids a problem (i.e., Mg++, Al+++, Ca++)?
No problem with normal kidney function. But a problem with impaired kidney function.
Mucosal Protective Agents Bismuth Subsalicylate:
This agent is used as a component of quadruple therapy to heal peptic ulcers.
Actions:
☛ antimicrobial actions.
☛ inhibits the activity of pepsin. ☛ increases secretion of mucus.
☛ and interacts with glycoproteins in necrotic mucosal tissue to coat and protect the ulcer.
Sucralfate
(a mucosal protective agent)
It binds to positively charged groups in proteins of both normal and necrotic mucosa in the ulcer crater.
By forming complex gels with necrotic cells in the ulcer, sucralfate coats mucosal defects.
It also stimulates prostaglandin, mucus, and bicarbonate release.
This allows the ulcer to heal.
Sulfate is negatively charged.
Gastric mucosa
Ulcer crater
Sucralfate
Sucralfate is effective for the treatment of duodenal ulcers and prevention of stress ulcers.
DISADVANTAGES:
It does not prevent NSAID-induced ulcers . It needs multiple daily dosing.
It requires an acidic pH for activation, therefore, sucralfate cannot be administered with PPIs, H2 antagonists, or antacids.
Sucralfate can interfere with the absorption of other drugs by binding to them.