ped2006-l1

• Gastrointestinal (GI) System


  Gastric acid secretion. Regulation and drugs which target secretary processes.
• Gastrointestinal importance


  Function: Major metabolic and endocrine system

  Pathology: Wide range of diseases

  Economic: £5 MILLION per year in Newcastle and North Tyneside
• Pharmacological importance


  Gastric secretion

  Vomiting (emesis)

  Bowel motility
• GI tract neuronal innervation

  • Nodose Ganglia
  • Muscle layers: Longitudinal, Circular
  • Intramural plexuses: Submucous / Meissners, Myentric / Auerbach's
  • Mucosa

  Brainstem

  Spinal cord

  Dorsal root Ganglia

  Vagus Nerve

  Pelvic / Splanchnic Nerve
• GI tract hormonal innervation

  • Endocrine secretions (bloodstream): Gastrin, Cholecystokinin

  Paracrine secretions (local): Histamine, Acetylcholine, Specialised cells
• HCI and Pepsin


  • Epithelium

  Lumen of Gland

  Mucus

  Chief Cells

  Parietal Cells

  Parietal Cells in the walls of the Gastric Gland
• Structure of Parietal Cell

  • Mitochondria

  Tubulovesicles

  Canalicular Membrane

  Basolateral Membrane

  Canaliculus
• Proton Pump action in the Canalicular Membrane


  PP

  C

  G

  H2M

  PG

  Histamine

  Gastrin

  ACh

  PGE2

  Vagus Nerve

  H+

  K+

  K+

  Cl-

  Gastric Lumen

  Parietal cell

  H+/K+ ATPase

  Cl- co-transporter

  Release isotonic HCL (pH <1)

  Requires extrinsic stimulation (hormones).
• Control of acid secretion

  • Gastrin: Peptide hormone, Stimulates acid secretion, pepsinogen secretion (indirectly), blood flow and increases gastric motility, Increases cytosolic Ca2+

  Acetylcholine: Neurotransmitter, Released from vagal neurones, Increases cytosolic Ca2+

  Histamine: Hormone, Sub-type specific action (H2 receptors), Increases cAMP
• Diseases associated with acid dysregulation


  • Dyspepsia (indigestion): Upper abdominal pain, bloating, nausea.

  Peptic ulceration: Prolonged excess acid secretion, gastric and duodenal ulceration

  Reflux oesophagitis: Damage to oesophagus by excess acid secretion

  Zollinger-Ellison syndrome: Gastrin producing tumour.
• Therapeutic aim


  • To decrease secretions of gastric acid by:

  Reducing proton pump function (proton pump inhibitors)

  Blocking histamine receptor function (H2 receptor antagonism)

  Neutralising acid secretions with antacids.
• Proton Pump Inhibitors (PPI's)


  Irreversibly inhibit H+/K+ ATPase

  Examples; omeprazole, lansoprazole

  Used in peptic ulcer, reflux oesophagitis, Zollinger-Ellison.

  Pharmacokinetics: Inactive at neutral pH, Weak bases – allows accumulation in acidic environment, Degrades rapidly at low pH (enteric coating), Single dosing - 2-3 day acid secretion inhibition
• Proton pump inhibitor binding
• Time to Activation Varies With pH
• Proton Pump Inhibitors Adverse effects

  • Uncommon: Headache, diarrhoea, rash.

  Can mask the symptoms of gastric cancer!

  Care must be taken in high risk groups i.e. Liver failure and pregnancy.
• Histamine H2 receptor antagonists


  Competitive inhibition of H2 histamine receptors

  Examples; cimetidine, ranitidine

  Used in peptic ulcer and reflux oesophagitis

  Pharmacokinetics: Rapidly absorbed orally, Dosage varies with condition, Potent inhibitor of cytochrome P450's
• Histamine H2 receptor antagonists Adverse effects


  • Rare: Diarrhoea, dizziness, muscle pain.

  Cimetidine has slight antiandrogenic actions.

  Potent inhibitor of cytochrome P450's – reduces metabolism of anticoagulants and tricyclic antidepressants.
• Antacids


  Bases that raise gastric luminal pH by neutralising gastric acid.

  Examples; Sodium bicarbonate, Mg2+/Al3+ hydroxide

  Uses; dyspepsia, oesophageal reflux.

  Pharmacokinetics: Relatively slow action, Effects often short lived, "Acid rebound"
• Antacids Adverse effects


  • Diarrhoea, Constipation, Belching, Acid rebound, Alkalosis

  Care must be taken with sodium content
• Helicobacter pylori infections


  • Gram negative bacillus

  Important factor in peptic ulcer formation.

  95% duodenal, 70% gastric ulcers

  Risk factor in gastric cancer

  Forms routine testing in patients with GI symptoms

  Urea breath test

  Treatment with combination (triple) therapy: PPI, antibacterials and cytoprotective agent.
• Cytoprotective agents


  • Enhance mucosal protection mechanisms or form barriers over ulcer formations.

  Examples:

  Bismuth Chelate: Toxic to bacillus, Coats ulcer base, prostaglandin and bicarbonate synthesis

  Sucralfate: Stimulates mucus production and prevents degradation, prostaglandin and bicarbonate synthesis

  Misoprostol: Prostaglandin analogue, Direct action on parietal cells (acid secretion)
• NSAID disruption of mucosa

  Prostaglandins: Synthesised by gastric mucosa (cyclo-oxygenase 1), Increase mucus and bicarbonate secretion, Decrease acid secretion

  Non steroidal anti inflammatory (NSAID's): Inhibit prostaglandin formation, Cause gastric bleeds, erosion, ulcer formation.

  Specific COX 2 inhibitors cause less GI damage
• Phospholipids in cell membrane

  • Phospholipase A2 (and related enzymes)

  Arachidonic acid

  Cyclo-oxygenase (COX)

  Various intermediates: prostacyclin, thromboxanes

  NSAIDS act here by inhibiting COX or its induction

  Glucocorticosteriods act here by inducing lipocortin, a protein inhibitor of phopholipase A2