Anti Ulcer Drugs

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Anti-ulcer drugs Professor Glenda Gillies

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Transcript of Anti Ulcer Drugs

  • Anti-ulcer drugs

    Professor Glenda Gillies

  • Learning Objectives Identify the factors that impinge on the development of peptic ulcer disease.

    Explain why antibiotics feature prominently in the treatment of peptic ulcer disease.

    Using named examples, explain, with the use of a clearly labelled diagram, the mechanisms by which proton pump inhibitors and histamine (H2) receptor antagonists promote the healing of gastric ulcers

    Explain why misoprostol may be used in the treatment of iatrogenic peptic ulcer disease.

    Explain the mechanisms by which sucralphate and bismuth chelate are thought to be useful anti-ulcer drugs.

    List two examples of triple therapy for peptic ulcer disease.

    Explain the term gastroesophageal reflux disease and how it may be treated.

  • Overview: Treatment of gastric & duodenal ulcers

    Background - physiology and pathology of the gastrointestinal barrier

    Drugs 1. Antacids 2. Inhibitors of gastric acid secretion 3. Cytoprotective drugs 4. Antibiotics and triple therapy

    Triple therapy

  • Peptic ulcer disease duodenal:gastric 4:1

    Area of damage to the inner lining of - the stomach (gastric ulcer)

    or - Upper part of the duodenum

    (duodenal ulcer)

    Pain at mealtimes, when gastric acid

    is secreted

    Pain relieved by a meal as pyloric sphincter closes; pain 2-3h after a

    meal

    Imbalance of factors which protect or damage gastointestinal barrier

  • Physiology: The integrity of the gastrointestinal mucosal barrier is important in maintaining a disease free state. Protective factors lubricate ingested food and protect the stomach and duodenum from attack by acid and enzymes:

    1. mucous from gastric mucosa creates gastrointestinal mucosal barrier

    2. HCO3- ions trapped in mucous generate a pH of 6-7 at mucosal surface

    3. locally produced prostaglandins stimulate mucous and bicarbonate production (paracrine action) and inhibit gastric acid secretion

  • Physiology: The integrity of the gastrointestinal mucosal barrier is important in maintaining a disease free state. Other factors which are needed to convert food

    into a thick semi-liquid paste (chyme) have the potential to damage the mucosal barrier:

    1. acid secretion from parietal cells of the oxyntic glands

    in the gastric mucosa

    2. pepsinogens from the chief cells which can erode the mucous layer

  • Mucus secreting cells cover the surface of the stomach

    Parietal (oxyntic) cell in human stomach (pink staining)

  • Pathogenesis: not fully understood

    Factors which may cause damage to mucosal gastrointestinal barrier

    Increased acid and/or decreased bicarbonate production

    Decreased thickness of mucosal layer Increase in pepsin type I Decreased mucosal blood flow Infections with Helicobacter pylori (discovered 1982)

  • Pathogenesis: not fully understood

    Risk factors: - genetic predisposition, - stress, - diet, alcohol, smoking Prevalence: - 1:10 of the population in developed countries

  • Endoscopy

    Gastric ulcer

    Duodenal ulcer Normal stomach

  • Aims of drug treatments

    - eliminate cause of mucosal damage

    - promote ulcer healing

  • Drug targets

    Drugs 1. Antacids 2. Inhibitors of gastric acid secretion 3. Cytoprotective drugs 4. Antibiotics and triple therapy

    Neutralise gastric acid

    Prevent gastric acid production

    Promote healing

    Eradicate H. pylori

  • 1. Antacids

    mainly salts of Na+, Al3+ and Mg2+ Sodium bicarbonate has rapid effects Aluminium hydroxide and magnesium trisilicate have

    slower actions neutralise acid, raises gastric pH, reduces

    pepsin activity taken orally; primarily used for non-ulcer

    dyspepsia may be effective in reducing duodenal ulcer

    recurrence rates

  • 2. Inhibitors of gastric acid secretion

    2.1. Proton pump inhibitors 2.2. Histamine type 2 (H2) receptor antagonists 2.3. Anti-muscarinics

  • CONTROL OF GASTRIC ACID SECRETION

  • Parietal cell oxyntic cell

    Vesicles storing the

    H+/K+ ATPase pump

    Membrane of the canaliculus

    Human stomach (pink staining)

  • Enterochromaffin/mast-like cells close to parietal cells in stomach

    Local cells

    Endocrine cells of mucosa

    PLASMA

    K+

    H+ STOMACH LUMEN 150mM HCl produced by active transport system

    PARIETAL CELL

    H+/K+ ATPase pump

  • ACh(M)

    Enterochromaffin/mast-like cells close to parietal cells in stomach

    Vagus + enteric

    neurones Local cells

    Endocrine cells of mucosa

    PLASMA ACh(M) H2

    K+ H+/K+ ATPase pump

    H+ LUMEN 150mM HCl produced by active transport system

    PARIETAL CELL

  • ACh(M)

    Enterochromaffin/mast-like cells close to parietal cells in stomach

    Vagus + enteric

    neurones Local cells

    Endocrine cells of mucosa

    PLASMA ACh(M) H2

    Adenylyl cyclase

    ATP cAMP Protein kinases

    K+ H+/K+ ATPase pump

    H+

    + Ca2+

    LUMEN

    150mM HCl produced by active transport system

    PARIETAL CELL

  • ACh(M)

    Enterochromaffin/mast-like cells close to parietal cells in stomach

    Vagus + enteric

    neurones Local cells

    Endocrine cells of mucosa

    G

    Gastrin secreted into bloodstream

    PLASMA ACh(M) H2 G

    Adenylyl cyclase

    ATP cAMP Protein kinases

    K+ H+/K+ ATPase pump

    H+

    + Ca2+ Ca2+

    LUMEN 150mM HCl produced by active transport system

    PARIETAL CELL

  • ACh(M)

    Enterochromaffin/mast-like cells close to parietal cells in stomach

    Vagus + enteric

    neurones Local cells

    Endocrine cells of mucosa

    G

    Gastrin secreted into bloodstream

    PLASMA ACh(M) H2 G

    Adenylyl cyclase

    ATP cAMP Protein kinases

    K+ H+/K+ ATPase pump

    H+

    + - Ca2+ Ca2+

    LUMEN 150mM HCl produced by active transport system

    PGE2

    PARIETAL CELL

  • 2.1. Proton pump inhibitors (PPIs)

    e.g. OMEPRAZOLE, inhibits basal and stimulated gastric acid secretion

    from the parietal cell by >90%

  • PPIs: mechanism of action

    PPIs are irreversible inhibitors of the H+/K+ ATPase

    inactive at neutral pH

    as it is a weak base it accumulates in the cannaliculi of parietal cells; this concentrates its action there and prolongs its duration of action (2-3 days) and minimises its effect on ion pumps elsewhere in the body

  • PPIs: uses

    uses component of triple therapy peptic ulcers resistant to H2 antagonists reflux oesophagitis

    orally active; administered as enteric coated

    slow-release formulations

    unwanted effects - rare

  • 2.2. Histamine type 2 (H2) receptor antagonists

    e.g. CIMETIDINE, RANITIDINE, inhibits gastric acid secretion by approximately

    60% and are less effective at healing ulcers than PPIs

  • Sir James Whyte Black, OM, FRS. FRSE, FRCP (14 June 1924 21 March 2010) Scottish doctor and pharmacologist; Nobel Laureate

    1964 Developed Propranolol 1972 Discovered histamine type-2 (H2) receptors and their antagonist, cimetidine; established a new principle in the treatment of peptic ulcer 1988 awarded the Nobel Prize for Medicine or Physiology in 1988 for these discoveries 2008 The Medical Futures Innovation Awards for Lifetime Achievement

  • H2 receptor antagonists

    orally administered, well absorbed unwanted effects rare >90% recurrence within 1 year after initial healing

  • ACh(M)

    Enterochromaffin/mast-like cells close to parietal cells in stomach

    Vagus + enteric

    neurones Local cells

    Endocrine cells of mucosa

    G

    Gastrin secreted into bloodstream

    PLASMA ACh(M) H2 G

    Adenylyl cyclase

    ATP cAMP Protein kinases

    K+ H+/K+ ATPase pump

    H+

    + - Ca2+ Ca2+

    LUMEN 150mM HCl produced by active transport system

    PGE2

    PARIETAL CELL

  • 2.3. Antimuscarinics

    Little use as anti-ulcer drugs

  • ACh(M)

    Enterochromaffin/mast-like cells close to parietal cells in stomach

    Vagus + enteric

    neurones Local cells

    Endocrine cells of mucosa

    G

    Gastrin secreted into bloodstream

    PLASMA ACh(M) H2 G

    Adenylyl cyclase

    ATP cAMP Protein kinases

    K+ H+/K+ ATPase pump

    H+

    + - Ca2+ Ca2+

    LUMEN

    150mM HCl produced by active transport system

    PGE2

  • 3. CYTOPROTECTIVE DRUGS

    These drugs enhance mucosal protection mechanisms and/or build a physical barrier over the ulcer

    3.1 Sucralfate 3.2. Bismuth chelate 3.3. Misoprostol

  • 3.1 Sucralfate: a polymer containing aluminium hydroxide and sucrose octa-sulphate How does it act? acquires a strong negative charge in an acid

    environment binds to positively charged groups in large

    molecules (proteins, glycoproteins) resulting in gel-like complexes

    these coat and protect the ulcer, limit H+ diffusion and pepsin degradation of mucus

    increases PG, mucous and HCO3- secretion and reduces the number of H. pylori

  • Sucralfate:

    What are its side effects? most of orally administered drug remains in g.i.t. may cause constipation reduces absorption of some other drugs (eg.

    antibiotics and digoxin)

  • 3.2. Bismuth chelate

    acts like sucralfate

    used in triple therapy (resistant cases)

  • 3.3. Misoprostol

    a stable prostaglandin analogue mimics the action of locally produced PG to maintain the gastroduodenal mucosal barrier

  • ACh(M)

    Enterochromaffin/mast-like cells close to parietal cells in stomach

    Vagus + enteric

    neurones Local cells

    Endocrine cells of mucosa

    G

    Gastrin secreted into bloodstream

    PLASMA ACh(M) H2 G

    Adenylyl cyclase

    ATP cAMP Protein kinases

    K+ H+/K+ ATPase pump

    H+

    + - Ca2+ Ca2+

    LUMEN

    150mM HCl produced by active transport system

    PGE2

  • Misoprostol

    May be co-prescribed with oral non-steroidal anti-inflammatory drugs (NSAIDs) when used chronically

    NSAIDs block the COX enzyme required for PG

    synthesis from arachidonic acid Therefore, there is a reduction in the natural

    factors that inhibit gastric acid secretion and stimulate mucus and HCO3- production

  • 3.3. Misoprostol

    Unwanted effects diarrhoea, abdominal cramps, uterine

    contractions do not use in pregnancy

  • 4. ANTIBIOTICS to eliminate Helicobacter pylori (Gram-negative bacterium)

    1982 H.pylori was discoverd as a new bacterium associated with ~100% of duodenal ulcers and ~80% of gastric ulcers Barry J. Marshall and J. Robin Warren Significant resistance to findings Marshall drank a bacterial culture of H.pylori and became seriously ill, with endoscopic investigations confirming dangerous inflammation of stomach lining. Successfully treated with antibiotics Findings were not accepted until 1994, at NIH consensus conference, Washington DC

  • Barry J. Marshall and J. Robbin Warren

    Barry J. Marshall receiving his Nobel Prize from His Majesty the King Carl XVI Gustaf of Sweden at the

    Stockholm Concert Hall, 10 December 2005.

    Summary This year's Nobel Laureates in Physiology or Medicine made the remarkable and unexpected discovery that inflammation in the stomach (gastritis) as well as ulceration of the stomach or duodenum (peptic ulcer disease) is the result of an infection of the stomach caused by the bacterium Helicobacter pylori.

  • Gastric biopsy Immunohistochemical stain

    Helicobacter pylori

    Scanning electron

    micrograph

  • Inclusion of antibiotics along with inhibitors of gastric acid secretion or cytoprotective agents in the treatment of peptic ulcers reduces relapse rates from >90% to
  • Rationale :

    50-80% of population worldwide are chronically infected (low grade infections cause gastritis)

    10-20% of which go on to develop peptic ulcer disease or neoplasia (mechanisms unknown - genetic/virulence of strain)

    almost 100% of patients with duodenal ulcer and 80-90% with gastric ulcer are infected

    Current therapy aims for 90% eradication within 7-14 days

  • Triple therapy is currently best practice in treating peptic ulcer disease

    A single antibiotic is not sufficiently effective - partly due to development of resistance

  • Example 1 metronidazole (active against anaerobic bacteria

    and protozoa) or amoxycillin (broad spectrum antibiotic), depending on pattern of local resistance

    clarithromycin antibiotics with a macrolide structure; inhibits

    translocation of bacterial tRNA) proton pump inhibitor (PPI)

    improves antibiotic efficiency possibly by increasing gastric pH which improves stability and absorption

  • Example 2 H2 receptor antagonists clarithromycin Bismuth Example 3 Metronidazole amoxycillin bismuth

  • 3 problems associated with triple therapy

    compliance development of resistance [vaccinations may

    soon be available] adverse response to alcohol, especially with

    metronidazole (interferes with alcohol metabolism)

  • Gastroesophageal Reflux disease (GERD)

    Stomach and duodenal contents reflux into the oesophagus (oesophagitis) - occasional and uncomplicated GERD - heart burn, may treat by self medication with antacids and H2 antagonists - chronically may progress to pre-malignant mucosal cells and potentially oesophageal adenocarcinoma

  • treat with PPIs (drugs of choice) or H2 antagonists (less effective)

    combine with drugs that increase gastric motility and emptying of the stomach eg. DA2 receptor antagonists (metoclopramide)

  • Key Points Identify the 3 main protective factors in maintaining the integrity of the upper GI tract and

    prevent ulceration

    Explain the role of antibiotics in the treatment if H. Pyloi and why this bacterium is significant in ulcer formation

    Explain using named examples, the mechanism of action of proton pump inhibitors and H2 antagonists in healing ulcers with the aid of a diagram

    Describe the mechanism of action of misprostol and its use in treatment of iatrogenic peptic ulcers

    Explain the mechanism of action of sucralfate and bismuth chelate in preventing peptic ulceration

    Explain the term GORD (gastroesopageal reflux disease) and the role of H2 antagonists and PPIs in its treatment with examples

  • Slide Number 1Learning ObjectivesOverview:Treatment of gastric & duodenal ulcers Peptic ulcer diseaseduodenal:gastric 4:1Physiology: The integrity of the gastrointestinal mucosal barrier is important in maintaining a disease free state.Physiology: The integrity of the gastrointestinal mucosal barrier is important in maintaining a disease free state.Slide Number 7Pathogenesis: not fully understoodPathogenesis: not fully understoodEndoscopyAims of drug treatmentsDrug targets1. Antacids 2. Inhibitors of gastric acid secretionSlide Number 15CONTROL OF GASTRIC ACID SECRETIONParietal celloxyntic cellSlide Number 18Slide Number 19Slide Number 20Slide Number 21Slide Number 222.1. Proton pump inhibitors (PPIs)PPIs: mechanism of actionPPIs: uses2.2. Histamine type 2 (H2) receptor antagonistsSir James Whyte Black, OM, FRS. FRSE, FRCP (14 June 1924 21 March 2010) Scottish doctor and pharmacologist; Nobel LaureateH2 receptor antagonistsSlide Number 292.3. AntimuscarinicsSlide Number 31Slide Number 323. CYTOPROTECTIVE DRUGS3.1 Sucralfate: a polymer containing aluminium hydroxide and sucrose octa-sulphateSucralfate:3.2. Bismuth chelate3.3. MisoprostolSlide Number 38Misoprostol3.3. Misoprostol4. ANTIBIOTICS to eliminate Helicobacter pylori (Gram-negative bacterium)Barry J. Marshall and J. Robbin WarrenSlide Number 43Inclusion of antibiotics along with inhibitors of gastric acid secretion or cytoprotective agents in the treatment of peptic ulcers reduces relapse rates from >90% to