Pharmacology

• Peptic ulcer

  A break in the mucosa of the stomach (gastric ulcer) or duodenum (duodenal ulcer)
• 4.5mil people in the USA suffer from peptic ulcer each year with 0.5mil new cases
• Aggravating factors for peptic ulcer disease

  • H. pylori infection
  • NSAIDs, Aspirin
  • Corticosteroids
  • Cigarette smoking
  • Alcohol
• Impaired defences leading to peptic ulcer disease

  • Ischemia, shock, stress related
  • Delayed gastric emptying
  • Duodenal-gastric reflux

  
• Mucosal defence factors


  • Surface mucus secretion
  • Bicarbonate secretion into the mucus
  • Mucosal blood flow
  • Apical Epithelial cell transport system
  • Epithelial regeneration capacity
  • Release of PGE and PGF
• Associated diseases with peptic ulcer disease

  • Cirrhosis
  • Chronic renal failure
  • Zollinger-Ellison syndrome
  • Hyperparathyroidism
  • Chronic lung disease
  • Chronic pancreatitis
• Clinical presentation of peptic ulcer disease

  • Abdominal Pain
  • Epigastric burning
  • Abdominal fullness or cramping
  • Nocturnal pain (12 midnight-3am)
  • Pain from Duodenal ulcers after meals
  • Food may relieve pain (Food may accentuate pain gastric ulcers)
  • Heartburn, belching, bloating, painful
  • Nausea, vomiting anorexia (more common in gastric ulcers than duodenal)

  
• Treatment plans for peptic ulcer disease

  • Gastric ulcers: PPI, H2-antagonists, Sucralfate, Bismuth compounds, Prostaglandin analogs
  • Esophageal ulcers: PPI, H2-antagonists
  • Duodenal ulcers: PPI, H2-antagonists

  
• Antacids


  Agents that Neutralize acids
• Types of antacids


  • Sodium bicarbonate
  • Calcium bicarbonate
  • Aluminium hydroxide
  • Magnesium hydroxide
• Sodium bicarbonate


  Reacts with HCl to produce carbon dioxide (CO2) and NaCl, causing gastric distension and belching. Can cause metabolic alkalosis in patients with renal insufficiency.

  
• Calcium carbonate


  Reacts slower than sodium bicarbonate, produces calcium chloride (CaCl2) and CO2, causing belching and metabolic alkalosis (milk-alkali syndrome). Excessive use can lead to hypercalcemia, renal insufficiency.
• Magnesium and Aluminium hydroxide

  Produce MgCl3 and AlCl3, no belching, rare metabolic alkalosis. Magnesium causes osmotic diarrhea, Aluminium causes constipation. Avoid long-term use in patients with renal insufficiency.
• Clinical uses of antacids

  • Gastroesophageal reflux disease (GERD)
  • Peptic ulcer disease

  
• H2-receptor antagonist


  Competitively Antagonize parietal cell H2 receptors, diminishing cAMP and resultant H+/K+ pump activity, blocking basal and meal-stimulated gastric acid secretion
• H2-receptor antagonist metabolism


  Famotidine is more potent than Cimetidine and Ranitidine
• Adverse effects of H2-receptor antagonists

  • CNS effects in the elderly (anxiety, headaches, dizziness, confusion)
  • Cimetidine - long-term use endocrine effects such as decreased libido, impotence and gynecomastia in men and galactorrhoea in women
  • Rapid infusion may cause bradycardia and hypotension
• Proton pump inhibitor properties

  • Benzimidazole structure
  • Omeprazole and Lansoprazole - mixtures R- and S- isomers, Esomeprazole - S-isomer of omeprazole
  • All are lipophilic weak bases (pKa 4-5)
  • Irreversibly binds to H+/K+-ATPase enzyme
  • Food affects bioavailability
  • First-pass metabolism - minimal renal clearance
• Proton pump inhibitors


  Inhibit both fasting and meal-stimulated acid secretion, standard doses inhibit 90-98% of 24h acid secretion compared to equivalent doses of other agents
• Clinical uses of proton pump inhibitors

  • Gastroesophageal reflux disease (GERD)
  • Peptic ulcer disease
  • H. pylori-associated ulcers
  • NSAID-associated ulcers
  • Prevention of re-bleeding from peptic ulcers
  • Prevents stress-related hyper-secretory conditions
  • Gastrinoma and other hyper-secretory conditions

  
• Adverse effects of proton pump inhibitors


  • Diarrhoea, headaches and abdominal pain
  • Reduction in cyanocobalamin absorption
  • Promotes absorption of food bound minerals, may reduce calcium absorption or inhibit osteoclast function
  • Elevations in gastric bacterial concentrations leading to Clostridium difficle, Salmonella, shigella, E. coli, Campylobacter infections
  • Decreased absorption of ketoconazole, itraconazole, increased absorption of digoxin, decreased absorption of atazanavir
  • Omeprazole may inhibit the metabolism of warfarin, diazepam, lansoprazole, enhance clearance of theophylline

  
• Sucralfate


  A salt of sucrose complexed to sulfated aluminium hydroxide that selectively binds to ulcers, forming a barrier to prevent further caustic damage and stimulate prostaglandin and bicarbonate secretion
• Prostaglandin analogs


  Increase bicarbonate secretion and enhance mucosal blood flow, can reduce the incidence of NSAID-induced ulcers to <3%

  
• Bismuth compounds

  Coat ulcers and erosions, bind enterotoxins (antimicrobial effect), used in H. pylori-associated ulcers as second line therapy

  
• Metoclopramide

  Prevents nausea and vomiting, inhibits cholinergic smooth muscle stimulation in the gastrointestinal tract
• Domperidone

  Prevents nausea, vomiting caused by other drugs used to treat Parkinson's Disease, inhibits cholinergic smooth muscle stimulation in the gastrointestinal tract
• Diphenoxylate

  Opioid agonist used to treat IBS or IBD, should not be used in patients with bloody stool
• Loperamide

  Opioid agonist (OTC) that does not cross the BBB, no analgesia, no potential for addiction, used to treat diarrhea
• Kaolin and pectin


  Kaolin is a clay-like powder that attracts and holds onto bacteria, pectin is a naturally occurring polysaccharide, used to treat diarrhea
• Other laxative agents


  • Osmotic Laxatives: Magnesium Hydroxide, Sodium Phosphate, Sorbitol Lactulose
  • Stimulant Laxatives: Anthraquinones Derivatives (Aloe, Senna), Diphenylmethane Derivatives (Bisacodyl)
  • Chloride Secretion activators: Lubiprostone
  • Opioid Antagonists: Alvimopan and Methylnaltrexone
  • 5-HT4-receptor agonists: Tegaserod