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YR1 - Pharmacology SEM 1 > 13. Regulation of Gastric Acid Secretion and the Treatment of Duodenal and Gastric Ulcers > Flashcards

13. Regulation of Gastric Acid Secretion and the Treatment of Duodenal and Gastric Ulcers Flashcards

1
Q

Where does the stomach lie?

What is its principal chemical activity?

What is the pH of the lumen of the stomach?

A

The Stomach

  • The stomach is part of the gastrointestinal tract and lies between the oesophagus and the duodenum
  • The principal chemical activity of the stomach is to begin the digestion of proteins, primarily through the action of pepsin
  • The stomach also has gastric acid and the lumen of the stomach has a pH 1-2
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2
Q

The stomach mucosa is exposed to some of the harshest conditions in the body. So why does the stomach not digest itself?

A

The Gastric Mucosal Barrier

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3
Q

What are 4 structural features of the gastric mucosal barrier that protects the stomach?

A

Gastric Mucosal Barrier - The gastric mucosal barrier protects the underlying tissue from the acid and enzymes in the lumen of the stomach

  1. Epithelial cells of the stomach mucosa are joined together by tight junctions which prevents gastric juice from reaching the underlying tissue
  2. Damaged epithelial cells are replaced very quickly
  3. Mucus secreted by surface epithelial cells coats the surface of the gastric mucosa
  4. Bicarbonate ions secreted by epithelial cells neutralise acid
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4
Q

Which cells in the stomach secrete gastric acid?

Which transporter is responsible for gastric acid?

Which molecules are exchanged and how is HCl made?

A

Gastric Acid - Parietal Cells

  • Parietal cells secrete gastric acid
  • The primary transporter responsible for the acid and acidity of the stomach is the H+/K+ ATPase (proton pump)
  • Parietal cells secrete a proton (H+) into the lumen of the stomach in exchange for a potassium ion (K+) into the parietal cell
  • Hydrochloric acid is formed when chloride ions (Cl-) move out through the Cl- channels into the lumen to maintain electro-neutrality
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5
Q

What are 3 enzymes that influence the secretion of gastric acid?

A

Mechanisms involved in gastric acid secretion

  1. Histamine
  2. Gastrin
  3. Acetylcholine
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6
Q

Which cells release Histamine in the GIT?

What receptors does histamine work on?

Effect?

A

Histamine

  • Released from enterochromaffin-like (ECL) cells (similar to mast cells) acts on histamine H2 receptors on parietal cells to stimulate acid release
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7
Q

Which cells release Gastrin in the GIT?

What receptors does gastrin work on?

Effect?

A

Gastrin

  • Released from G cells in the gastric glands acts on gastrin receptors on parietal cells to stimulate acid release
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8
Q

What secretes Acetylcholine and what is the effect on gastric acid secretion?

A

Acetylcholine

  • Released from parasympathetic post ganglionic nerve fibres acts on muscarinic M3 receptors on parietal cells to stimulate acid release
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9
Q

What is a peptic ulcer? Types?

A

Peptic Ulcers

  • Ulcers may occur in the stomach and duodenum when the integrity of the mucosal barrier is reduced, and the underlying tissues are exposed to the acid and enzymes
  • Ulcers which occur in the stomach are called gastric or stomach ulcers
  • Ulcers which occur in the duodenum are called duodenal ulcers
  • Peptic ulcer is a generic term and is used to describe both gastric and duodenal ulcers
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10
Q

What are the two main causes of gastric and duodenal ulcers?

A

The two main causes of gastric and duodenal ulcers are:

  1. Infection with Helicobacter pylori
  2. The longer term use of non-steroidal anti-inflammatory drugs (NSAIDs)
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11
Q

How many people in Australia are infected with H.pylori?

A

H.pylori Epidemiology

In Australia approximately 40% of adults and 10% of children are infected with H.pylori

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12
Q

What are 4 routes of transmission of H.pylori?

A

H.pylori - Transmission

  1. Mouth to mouth contact – eg. Kissing
  2. Sharing foods or utensils with an infected person
  3. Contact with vomit or faeces of an infected person
  4. Contaminated food or water
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13
Q

What features of H.pylori allow it to live in the inhospital environment of the stomach?

A

Helicobacter pylori (H.pylori)

  • It is a spiral, flagellated, motile, gram negative rod (bacteria) which lives at the gastric mucosal surface
  • It can survive these inhospitable conditions because it releases urease, an enzyme which converts urea in the stomach to ammonia and carbon dioxide
  • This raises the pH of the local environment
  • Being motile also allows H.pylori to move to areas of the mucosa which have a more neutral pH
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14
Q

How does Helicobacter pylori cause ulcers?

A

Peptic Ulcers & H.pylori - Pathophysiology

  • Helicobacter pylori is a bacteria which lives at the gastric mucosal surface
  • Infected epithelial cells release cytokines which recruit leukocytes and other inflammatory cells to the area
  • This can result in gastritis and active inflammation, and lead to an active, inflammatory infiltration of the gastric mucosa which can result in epithelial cell damage and death
  • This may expose the underlying tissue to acid and enzymes and result in ulceration
  • Some evidence also suggests that H.pylori may increase gastrin release and cause prolonged acid secretion
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15
Q

What percentage of duodenal ulcers are H.pylori responsible for?

What percentage of gastric ulcers are H.pylori responsible for?

A

Helicobacter pylori (H.pylori)

  • H pylori is the cause of about 90% of duodenal ulcers
  • H pylori is the cause of about 70% of gastric (stomach) ulcers
  • H pylori infection may also increase the risk of stomach cancer
  • However, most people with H.pylori infection have no symptoms and do not get ulcers (they may have inflammation of the stomach lining)
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16
Q

How can H pylori be detected?

A

Urea Breath Test for H pylori

  • C13 or C14 urea breath tests
  • The patient swallows a capsule containing carbon labelled urea (C13 or C14)
  • If H pylori is present the labelled urea is metabolised to labelled carbon dioxide and ammonia by the enzyme urease, produced by H pylori
  • The labelled carbon dioxide diffuses into the blood and is excreted by the lungs where it can be detected in the exhaled breath
  • If H pylori is absent labelled carbon dioxide is not produced
  • Although the C13 urea breath test is more expensive, it is not radioactive and is preferred for children and women of childbearing age
  • Before a breath test antibiotic therapy should not be taken for at least 4 weeks, PPI therapy should be withheld for at least 1 week (and preferably 2 weeks), and H2 antagonists should be withheld for 72 hours prior to the test to minimise the chance of a false negative result
17
Q

What is the Treatment for H.pylori infection?

A

Treatment of Helicobacter pylori Infection

  • Triple therapy is used - amoxicillin, clarithromycin and esomeprazole
    • amoxicillin has a bactericidal effect on H. pylori
    • clarithromycin has a bacteriostatic effect on H. pylori
    • PPIs suppress, but do not eradicate H. pylori
  • Triple therapy is taken for 7 days and the eradication rate is at least 90%
  • Eradication of H. pylori is associated with long term remission of peptic ulcer disease
18
Q

Who was Ötzi the Iceman?

A

Ötzi the Iceman

  • Ötzi the Iceman is a famous, naturally created mummy who was discovered in 1991
  • He died around the year 3,300 B.C.
  • It has now been revealed that the Iceman was infected with Helicobacter pylori, a common gut bacteria that can cause stomach ulcers
19
Q

What are the 2 categories of NSAIDs?

Examples of each?

A

Nonsteroidal Anti-inflammatory Agents (NSAIDS)

  • Traditional NSAIDS
    • Aspirin
    • Diclofenac
    • Ibuprofen
    • Naproxen
  • COX 2 inhibitors
    • Celecoxib
    • Meloxicam
20
Q

What 2 products does Arachidonic acid form?

2 enzymes involved?

A

Arachidonic Acid

  1. Prostaglandins (cyclooxygenase)
  2. Leukotrienes (5-Lipoxygenase)
21
Q

Cyclooxygenase exists in what 2 forms?

A

Nonsteroidal Anti-inflammatory Agents (NSAIDS)

Cyclooxygenase exists in two forms

  • cyclooxygenase 1 (COX 1)
  • cyclooxygenase 2 (COX 2)
  • Some evidence that other forms may also exist e.g. COX 3, but their location and function are not well understood
22
Q

Where is COX1 found? Function?

Where is COX2 found? Function?

A

NSAIDs & Cyclooxygenase

  • COX is found in most cells
    • It is a constitutive enzyme which synthesises the production of prostaglandins which are involved in homeostasis - “housekeeping” or “good” prostaglandins
  • COX 2 is also a constitutive enzyme in some areas e.g. kidney, vascular tissue
    • COX 2 is induced by inflammatory stimuli and synthesises prostaglandins which are involved in pain and inflammation - “bad” prostaglandins
23
Q

Which COX do Traditional NSAIDs inihibit?

What is the issue with this?

A

Peptic Ulcers & NSAIDS

  • Traditional NSAIDS (e.g. aspirin, diclofenac, ibuprofen, naproxen) inhibit both COX 1 and COX 2
  • Traditional NSAIDS block the production of all prostaglandins
  • Traditional NSAIDS thus block the production of both “bad” prostaglandins and “good/housekeeping” prostaglandins
  • Examples of “housekeeping” prostaglandins include those that
    • help maintain mucosal gastric protection and reduce gastric acid secretion e.g. PGE2, PGI2 (COX 1)
24
Q

What does the mucosal barrier in the stomach and duodenum do?

What are 4 ways that prostaglandins formed by COX1 help to maintain this protective barrier?

A

Prostaglandins and the mucosal barrier

  • The mucosal barrier (bicarbonate and mucus) protects the underlying tissue from the acid and enzymes in the lumen of the stomach/duodenum
  • Prostaglandins formed by COX 1 (e.g. PGE2) help maintain this protective barrier by:
    1. ↑ bicarbonate ion secretion
    2. ↑ mucus secretion
    3. ↑ mucosal blood flow
    4. ↓ gastric acid secretion
25
Q

How can NSAIDs lead to peptic ulcers?

A

NSAIDS & Peptic Ulcers - Pathophysiology

  • Traditional NSAIDS inhibit COX 1
  • They may reduce the production of prostaglandins formed by COX 1 (e.g. PGE2) which help to maintain the mucosal barrier
  • Inhibition of COX 1 by NSAIDS may reduce the effectiveness and integrity of the Gastric Mucosal Barrier (effect of selective COX 2 inhibitors?)
  • This may expose the underlying tissue to the acid and enzymes in the lumen of the stomach and duodenum
  • Longer term NSAID use may result in mucosal damage, bleeding and peptic ulcers
26
Q

What are 4 Pharmacological Treatments for Duodenal and Stomach Ulcers?

A

Pharmacological Treatments for Duodenal and Stomach Ulcers

  1. Histamine H2 receptor blocking agents (H2 Blockers)
  2. Proton pump inhibitors (PPIs)
  3. Triple therapy
  4. Antacids
27
Q

What are 3 examples of H2 receptor antagonists?

Mechanism of Action?

Indications?

A

Histamine H2 Receptor Blocking Agents (H2 Blockers)

  • Examples
    1. Cimetidine
    2. Ranitidine
    3. Famotidine
  • Mechanism of Action
    • They are competitive antagonists of histamine at histamine H2 receptors
    • By inhibiting the action of histamine at H2 receptors on the parietal cell they reduce the secretion of gastric acid
  • Indications:
    • gastric and duodenal ulcers
    • dyspepsia and reflux oesophagitis (heart burn, GORD)
  • In general histamine H2 receptor blockers are well tolerated
  • Cimetidine has many drug interactions and is seldom used now
  • Ulcers may recur after treatment is stopped (H pylori, triple therapy)
28
Q

What are 3 examples of Proton Pump Inhibitors (PPIs)?

Mechanism of Action?

Indications?

A

Proton Pump Inhibitors (PPIs)

  • Examples:
    1. omeprazole
    2. esomeprazole (S-isomer of omeprazole)
    3. pantoprazole
  • Mechanism of Action:
    • They bind to H+/K+ ATPase and inhibit the proton pump
    • Produce a potent and long lasting suppression of basal and stimulated gastric acid secretion
    • As they act distal to the receptors they can reduce gastric acid secretion irrespective of the stimulus (acetylcholine, histamine or gastrin)
  • Indications:
    • gastric and duodenal ulcers
    • dyspepsia and reflux oesophagitis (heart burn, GORD)
  • They are one of the most widely used drug groups in Australia
  • In general PPIs are well tolerated
  • Ulcers may recur after treatment is stopped (H pylori, triple therapy)
29
Q

What are 2 conditions associated with longer term use of PPIs?

A

PPIs - Long term use

Longer term therapy may be associated with an increased risk of:

  1. Osteoporosis
  2. Clostridium difficile infection
30
Q

What are Antacids used for?

Mechanism of Action? (+ chemical equation)

2 Adverse Effects?

A

Antacids

  • Indications:
    • dyspepsia and reflux oesophagitis (heart burn, GORD)
    • symptoms of gastric and duodenal ulcers (heal ulcers?)
  • Mechanism of Action:
    • Neutralise excessive gastric acid, raise pH and give rapid relief
    • Contain substances such as calcium carbonate, magnesium hydroxide and aluminium hydroxide
  • Adverse effects:
    • Aluminium salts may cause constipation
    • Magnesium salts may cause diarrhoea

YR1 - Pharmacology SEM 1 (14 decks)

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