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Gastrointestinal Tract

GItracct2.PNG

  • Disorders of the upper GI tract
    • Gastroesophageal reflux disease (GERD/GORD)
    • Peptic ulcer disease (PUD)
    • Dyspepsia
  • Disorders of the lower GI tract
    • Inflammatory bowel disease (IBD)
    • Diarrhoea
    • Constipation
    • Irritable bowel syndrome (IBS)'

Objectives

  • Understand the process of gastric acid secretion and the rationale underlying pharmacological treatments of GERD/PUD/dyspepsia
  • Understand the pathophysiology and therapeutics of IBD
  • Be able to describe the medications used in gastrointestinal motility disorders

Disorders of the Upper GI Tract

  • Gastroesophageal reflux disease (GERD)
  • Peptic ulcer disease (PUD)
  • Dyspepsia
  • In Australia: approx 1 in 4 or 22% of total population suffer from GI diseases
  • GERD and PUD cost the nation $17 billion per annum - or $8,000 for every patient

Gastroesophageal reflux disease (GERD)

  • Abnormal reflux of gastric contents into oesophagus
  • Prevalence:
    • > 50% of population at least once a year
    • 50% of patients have erosive oesophagitis
  • Pathophysiology: Delayed gastric emptying, decreased LES tone, increased frequency of transient Les relaxation
    • age lowers LES tone. Eating too much forces through LES
    • oesophagus mucosa pH 7; stomach pH 2
  • Symptoms and signs: heartburn, regurgitation
  • Complications: oesophageal ulcers, Barrett’s esophagus (can lead to cancer due to epithelial metaplasia - oesophageal epithelium becomes stomach type), cancer

Peptic ulcer disease (PUD)

  • Peptic ulcer: a sore (lesion) on the lining of the stomach or duodenum. The ulcer extends all the way through epithelial, lamina propria and muscularis mucosae
  • Prevalence: 5-10%
  • Aetiology (most common):
    • inflammation caused by Helicobacter pylori infection
    • long-term use of NSAIDs e.g. aspirin and ibuprofen
  • Symptoms: Epigastric pain (gnawing, dull, empty or hunger-like). hard to distinguish from PUD
  • Complications: GI hemorrhage, perforation (high mortality rate), gastric outlet obstruction

Dyspepsia

  • Dyspepsia (stomach discomfort), a condition of impaired digestion
  • Prevalence 25-40%
  • Aetiology
    • Organic dyspepsia: Is frequently associated with GERD, gastritis or PUD. Medication induced (NSAIDs, glucocorticoids, iron, sildenafil)
    • Functional (nonulcer) dyspepsia: no obvious cause and pathophysiology
  • Clinical features of dyspepsia, GERD and gastritis overlap, making diagnosis difficult
    • "the food can't go down, stuff is stuck in my stomach"

Treatment strategies for GERD/PUD/dyspepsia

  • Goals:
    • Relieve symptoms
    • Heal oesophogitis, ulcers
    • Maintain remission
    • Prevent complications

Gastric Acid Secretion

Gastric cells.PNG

  • Gastric cells
    • Histamine, ACh, Gastrin activates gastric cells,
    • KCl into cell
    • H+ activates pepsinogen --> pepsin for digestion of proteins

Reducing Acid Secretion

  • high protein meal causes parietal cell to become stimulated
  • low pH activates pepsinogen to pepsin to allow it to chop up proteins
  • ACh blockers not used unless nothing else works (ACh widespread)

Reducing gastric secretion.PNG

  • Antacids
    • Weak bases
      • Aluminum hydroxide (cause constipation);
      • Magnesium hydroxide (cause diarrhoea); often combined
        • Al(OH)3 + 3HCl ---> AlCl3 + 3H2O
        • Mg(OH)2 + 2HCl ---> MgCl2 + 2H20
  • Relieve symptoms in 5 to 15 minutes by neutralising stomach acid.
  • Work well to relieve occasional mild heartburn but aren't as helpful in preventing it
  • Anti-acid secretion agents
    • H2-receptor antagonists – competitive and selective inhibition of histamine H2 receptors
    • Cimetidine (Tagamet®, first H2 blocker available)
      • Not used often due to drug interactions
    • Ranitidine (Zantac®): 150-300 mg oral bid
    • Famotidine (Pepcid®): 20-40 mg oral bid
    • Nizatidine (Axid®): 150-300 mg oral bid
    • H2-receptor antagonists suppress 24 hr gastric secretion by 70% (less effective than PPI)
      • Given for 6 weeks; 85% healing at 2 months
      • If stop treatment - 90% recurrence at 2 years
    • Clinical uses: GERD, PUD, dyspepsia, prevention of stress related mucosal bleeding
    • Caution for drug interaction when using cimetidine, as cimetidine inhibits CYP450 and reduces oxidative drug metabolism (e.g. warfarin, phenytoin or theophylline)
  • Proton Pump Inhibitors (PPI)
    • Inhibit gastric H+/K+/ATPase (proton pump) irreversibly
    • Decrease acid secretion by up to 95% for up to 48 h
    • 90 - 100% healing at 2 months
    • Low recurrence on long term maintenance
    • Steadily replace H2 antagonists
    • Clinical uses: GERD, PUD, dyspepsia, prevention of stress related mucosal bleeding, Zollinger-Ellison syndrome (gastrinoma)
    • Side effects: Generally well tolerated, headache, dizziness; may increase risk of GI infections (reduced acidity); Omeprazole may cause impotence
    • Doesn't have local effect in stomach, but instead is dissolved into blood

H. Pylori Eradication

  • Nexium Hp7: Esomeprazole (20 mg): Amoxycillin (1000mg), Clarithromycin (500 mg). 7 days, twice daily
  • KLACID Hp7: Omeprazole (20 mg), Amoxycillin (1000 mg), Clarithromycin (500 mg). 7 days, twice daily
    • Amoxicillin: inhibits the making of the bacterial cell wall
    • Clarithromycin: inhibits the making of bacterial proteins
    • Esomeprazole and omeprazole: inhibits acid secretion
  • 80-90% of patients will become cured of bacteria and ulcers
  • Low recurrence after eradication treatment since infections mainly occur in childhood
  • Why do some not get cured? Poor compliance or bacterium is resistant to antibiotics

Prostaglandin analogs

  • Misoprostol, a synthetic prostaglandin E1 analogue.
  • an EP agonist, stimulates mucus and bicarbonate secretion and enhance mucosal blood flow (mucosal defense and cytoprotection effects)
  • It inhibits cAMP and reduces gastric acid secretion
  • Clinical uses: used in NSAIDs induced ulcers
  • Side effects: Diarrhoea and cramping abdominal pain. Avoid during pregnancy since misoprostol stimulates uterine contractions

Disorders of the Lower GI Tract

  • Inflammatory bowel disease (IBD)
  • Diarrhoea
  • Constipation motility disorders
  • Irritable bowel syndrome (IBS)

Inflammatory bowel disease

  • Ulcerative Colitis (UC): characterized by remitting and relapsing inflammation of the large intestine. The ulcers are constrained in the mucosa region of the colon
  • Crohn’s disease (CD): an ongoing disorder, patchy transmural inflammation, may affect any part of GI tract; often starts at ileum; extra-GIT symptoms
    • Affects rate of colon cancer
  • Features:
    • UC: bloody diarrhoea, crampy abdominal pain, urgency, tenesmus, anemia
    • CD: abdominal pain, diarrhoea, weight loss, intestinal obstruction, systemic symptoms

IBD.PNG

  • Around 65,000 Australians live with IBD
  • The number is increasing every year
  • IBD has an onset in early adulthood and a life long impact
  • Altogheter, the financial and disease burden of IBD is estimated to cost $2.7 billion per annum
  • Aetiology:
    • Autoimmune disease: The continued abnormal activation of the immune systems causes chronic inflammation.
    • Genetic predisposition: First degree relatives of patients with IBD have higher incidence rate. 12 regions of the genome may be linked to UC (chromosomes 16, 12, 6, 14, 5, 19, 1, 16, and 3). CD is associated NOD2/CARD15 gene variants.
    • Altered enteric microflora components: Distinct strains of Escherichia coli have been identified as a cause of CD; these strains secrete enterotoxins and produce dysregulation of the mucosal immune system
    • Environmental factors: diet, smoking etc. Breastfeeding may be protective.
      • not the cause - just facilitating factors

Case Study

  • A 57 year-old male presents to the hospital with severe bloody diarrhoea. He complains of passing stools more than 10 time daily with crampy abdominal pain and uncontrollable urgency. He appears pale and thin. On examination, he is anaemia and has low serum albumin levels
  • The endoscopic examination shows confluent superficial ulceration, and loss of mucosal architecture.

Casestuoody.PNG

  • Diagnosis: ulcerative colitis affecting the left side of the colon

Step 1 Drugs for IBD

  • 5-Aminosalicylic acid derivatives (5-ASA)e.g. sulfasalazine; mainstay of management of IBD.
  • Sulfasalazine is metabolized to 5-ASA, and sulfapyridine in the intestine. 5-ASA is a salicylate, but its therapeutic effect appears unrelated to cyclooxygenase inhibition, rather is associated with inhibition of production of inflammatory cytokines, e.g. IL-1 and TNFα and NF-κB.
  • Side effects (nausea, vomiting, heartburn, diarrhoea, and headache) are mainly caused by sulfapyridine.
  • Other 5-ASA agents, such as mesalazine have fewer side effects
  • 5-ASA drugs are more effective for UC than (colonic) CD. Use for flare-ups and maintaining remission.

Step 2 Drugs for IBD

  • Corticosteroids
    • For acute flare-ups only, no role in maintaining remission
    • Prednisone, a synthetic corticosteroid drug; converted by the liver into the active form of steroid prednisolone.
    • Prednisone reduces inflammation and suppresses the immune system.
    • Prednisone causes many side effects such as weight gain, facial hair, hypertension, diabetes, mood swings, bone mass loss, and an increased risk of infection. Not recommended for long-term use

Step 3 Drugs for IBD

  • Immunomodulatory agents:
    • 6-mercaptopurine (6-MP) and azathioprine
      • Slow onset of action
      • Used to treat fistulae, maintain remission in patients who do not respond to 5-ASAs or corticosteroids or who are dependent on corticosteroids.
      • Use must be closely monitored
      • Side effects are numerous
      • Question of increased risk of malignancy(especially lymphoma)
    • Infliximab
      • Anti-TNF-α (tumour necrosis factor- α) monoclonal chimeric (mouse-human) antibody administered by infusion for the treatment of CD and most recently, UC
      • Variable duration of response (weeks to months)
      • Numerous side effects including risk of infection (particularly tuberculosis)
      • Useful to close fistulae and treat perianal disease
      • Reduced requirement for surgery

Diarrhoea

  • Definition = Passage of unusually loose or liquid stools 3 times or more per day (recent change in consistency)
  • Causes of diarrhoea
    • Acute: infection (Salmonella, shigella, E. coli); drug induced, nutritional, anxiety or stress
    • Chronic: Tumours, IBD, IBS, diabetes, hyperthyroidism
  • A principal cause of death in children due to excessive loss of water and electrolytes
  • Management of diarrhoea
    • Maintenance of fluid and electrolyte balance
    • Treat the causes: e.g. drugs for IBD, anti-infective agents
    • Antimotility drugs: opioids, μ-receptor agonists
      • Morphine, codeine, diphenoxylate (all have CNS effects)
      • Loperamide (Imodium), first line antidiarrhoeal drug
        • 50 times more potent than morphine
        • Peripheral action (little/no CNS side effects)
        • Decreases motility and increases transit time; antisecretory against cholera toxin and some E. Coli toxin
        • Risk to develop paralytic ileus (not used <2 years old).
        • Cautions in dysentery (bloody diarrhoea), and in IBD (toxic megacolon)
      • NB: Antimotility drugs treat symptoms only!

Constipation

  • Definition = Unsatisfactory defecation that results in infrequent stool, difficult stool passage, or both
  • Causes of constipation
    • GI disorders: IBS, hernia, anal fissures
    • Metabolic: Diabetes with neuropathy, hypothyriodism
    • Psychogenic
    • Medications (analgesics, antacids, iron preparations)
    • Idiopathic
    • Affect ~30% populations
  • Management of constipation
    • Life style management:
      • Fibre rich diet, fluid
      • Avoid drugs that can cause constipation
    • Pharmacological treatment:
      • Bulk and osmotic laxatives:
        • Methylcellulose, magnesium sulfate/magnesium hydroxide, lactulose , sorbitol
        • Increases colonic mass which triggers peristalsis
        • Increases water content of stool via hydrophilic forces
      • Faecal softeners: mineral oil, docusate sodium
      • Stimulant purgatives: Bisacodyl, senna
        • Induce low-grade inflammation in the small and large intestine to promote accumulation of water and stimulate motility
      • Side effects: abdominal distension, cramps, diarrhoea, hypokalaemia

Irritable Bowel Syndrome

  • IBS, a functional colonic motility disorder, refers to recurrent abdominal pain with disturbed bowel habits.
  • 9-12% of population affected; women more than men
  • Aetiology (largely unknown)
    • ?Pathophysiology
    • Dysregulation of “brain-gut axis“ (modulation of visceral afferences and efferences, psychosocial factors)
    • Abnormal GI-reactivity (internal and external stimuli)
    • GI-hypersensitivity (pain and visceral perception)

Sub-Types

  • Constipation-Predominant IBS-C
    • Stool frequency <3x/week
    • Hard stools
    • Straining upon defecation
  • Diarrhoea-Predominant IBS-D
    • Stool frequency >3x/day
    • Soft / liquid stools
    • Imperative urge
  • Alternating-Predominant IBS-A
    • At least one change between IBS-C and IBS-D per year

IBS Tx.PNG