GI Pharmacology Part 1 PDF

GASTROINTESTINAL PHARMACOLOGY Gastrointestinal Tract Stomach Gastric Rugae (Folds) Coiled sections of tissue in the mucosal and submucosal layers of the stomach Provide - elasticity for stomach expansion via mechanoreceptors responding to increased pressure when bolus of food enters - the stomach wi...

GASTROINTESTINAL PHARMACOLOGY Gastrointestinal Tract Stomach Gastric Rugae (Folds) Coiled sections of tissue in the mucosal and submucosal layers of the stomach Provide - elasticity for stomach expansion via mechanoreceptors responding to increased pressure when bolus of food enters - the stomach with increased surface area for nutrient absorption during digestion Stomach Lining Gastric Glands Stomach Lining Stomach Lining Mucous Cells AKA Foveolar Mucus-producing cells which cover the inside of the stomach Protects from the corrosive nature of gastric acid Line the gastric mucosa Found in the necks of the gastric pits Parietal Cell: Acid Secretion Responsible for gastric acid secretion Aids in the digestion of food, absorption of minerals, and control of harmful bacteria Enterochromaffin-like cells or ECL cells Neuroendocrine cell found in the gastric glands of the gastric mucosa beneath the epithelium primarily is close to parietal cells Aid in the production of gastric acid via the release of histamine Receive stimulus of - G-cells - Vagus nerve 1) Pituitary adenyl cyclase activating polypeptide (PACAP) 2) Gastrin-release peptide Gastric Chief Cell: Synthesis and Production of Pepsin AKA zymogenic or peptic cells Releases pepsinogen and chymosin Pepsinogen is activated into the digestive enzyme pepsin when it comes in contact with hydrochloric acid produced by gastric parietal cells HCl +HCl Pepsin Pepsin G-cells Neuroendocrine cells responsible for the synthesis and secretion of gastrin Mainly found in the pyloric antrum Also present in the duodenum and pancreas They secrete gastrin when stimulated directly by vagal efferent neurons as well as GRP neurons Delta (D) Cells Dispersed throughout the whole gastrointestinal tract Produce somatostatin, AKA growth hormone inhibiting hormone Produced in many locations: GI track, pancreas, hypothalamus, Has inhibiting effects on the production of acid in the stomach, the motor activity of the intestine, and the release of digestive enzymes from the pancreas Enterochromaffin (EC) Cells Neurogenic cells dispersed throughout the stomach Contain secretory granules that release serotonin (pleomorphic/rod-like) , key neurotransmitter in stomach Released by many types of stimuli, most potently by mucosal stroking Serotonin stimulates enteric nerves to initiate secretion and propulsive motility Rapidly destructed in the blood, particularly in the liver Enterochromaffin (EC) Cells Gastric Mucosal Barrier Thick, alkaline-rich mucus secretion of mucosal cells in the pyloric region - protects the epithelium of the stomach and duodenum from harsh acid conditions Stimulated by mechanical and chemical irritation and parasympathetic innervation Susceptible to bacterial and viral infection, certain drugs, and aspirin Conditions Gastroesophageal Reflux Disease (GERD) Backflow of stomach acid into the esophagus Normally the lower esophageal sphincter (LES) relaxes to allow food and liquid to flow into your stomach, then the sphincter closes again If the sphincter does not relax as it should or it weakens, stomach acid can flow back into your esophagus Esophagus is not equipped to handle stomach acid => scaring Usual symptom is heartburn, an uncomfortable burning sensation behind the sternum (MI often mistaken for GERD !) Gastroesophageal Reflux Disease (GERD) More severe symptoms: difficulty swallowing, chest pain Reflux into the throat can cause sore throat Complications include esophageal erosions, esophageal ulcer and narrowing of the esophagus (esophageal stricture) In some patients (~10%), the normal esophageal lining or epithelium may be replaced with abnormal (Barrett's) epithelium. This condition (Barrett's esophagus) has been linked to cancer of the esophagus Gastroesophageal Reflux Disease (GERD) Endoscope of Barrett’s Esophagus (can become malignant - needs monitoring) Gastroesophageal Reflux Disease (GERD) Precipitants: Food (fatty food, alcohol, caffeine) Smoking Obesity Pregnancy Usually chronic relapsing course Peptic Ulcer Disease (PUD) Benign PUD: Normal gastric acid production however the mucosal barrier is weak Malignant PUD: Excessive secretion of gastric Acid that overwhelms the mucosal barrier. Treatment of Heartburn, GERD and PUD Antacids H2 Receptor Blockers Mucosal Protective Agents Proton Pump Inhibitors Anti-cholinergics Prostaglandin Analogs Anti-microbial Agents Antacids Systemic Antacid: Sodium Bicarbonate Non systemic Antacid: not absorbed into systemic circulation and do not produce systemic alkalosis - Aluminum Hydroxide + Magnesium Hydroxide Combinations (Maalox and Mylanta) - Contraindicated in patients with impaired renal function - Magnesium may cause diarrhea - Calcium Carbonate (Tums) – Calcium may cause constipation ANTACID NEUTRALIZING CAPACITY (ANC) Amount of 1N HCl (36.5 grams of HCl per liter, meq) brought to pH 3.5 by an antacid solution within 15 min FDA requires a Min= 5 meq/dose of ANC As the ANC number increases the neutralizing capacity of an antacid increases Maalox TC=28 Mylanta DS=23 Tums EX=15 Histamine H2 Receptor Blockers Inhibit secretion of gastric acid through competitive inhibition (reversable) of Histamine H2 receptors at parietal cells Prevention and Tx of GERD, PUD, Esophagitis, GI bleeding, stress ulcers, and Zollinger-Ellison Syndrome (gastrinoma commonly in pancreas and duodenum, which causes hypersecreting gastric acid, ulcer esophagus, stomach, and duodenum, diarrhea, and heartburn) PM/HS administration Cimetidine Famotidine Ranitidine Nizatidine Histamine H2 Receptor Blockers Very few side effects (except for cimetidine inhibits metabolism of estrogen) Suppresses 24 hour gastric secretion by 70% FDA decided removed ranitidine (Zantac),from the market because they found that could potentially cause cancer Cimetidine Famotidine Ranitidine Nizatidine Proton Pump Inhibitors Strong inhibitors of gastric acid secretion through irreversible inhibition of proton pump, preventing “pumping” or release of gastric acid (24 hr action) Indicated in PUD, GERD, Gastritis,, & ZollingerEllison syndrome Faster relief and healing than H2 receptor blockers Decreases acid secretion by up to 95% for up to 48 hours 4-8 week course of treatment Omeprazole Pantoprazole Lansoprazole Esomeprazole Rebeprazole Misoprostol Synthetic prostaglandin E1 analog that stimulates prostaglandin E1 receptors on parietal cells in the stomach to reduce gastric acid secretion Mucus and bicarbonate secretion are also increased along with thickening of the mucosal bilayer so the mucosa can generate new cells Tx of NSAID induced injury Side effects include diarrhea, pain, and cramps (30%) Do not give to women of childbearing years unless pt is on a reliable method of birth control Can cause birth defects, and premature birth Pirenzepine Anticholinergic Muscarinic M1 acetylcholine receptor antagonist Blocks gastric acid secretions About as effective as H2 blockers Rarely used, primarily as adjunct therapy Anticholinergic side effects (anorexia, blurry vision, constipation, dry mouth, sedation) Summary of Acid Reduction Treatments Antacids H+ Cl- Mucosal Protective Agents Sucralfate (carafate) Can be used to prevent & treat PUD It requires an acid Ph to activate Forms sticky polymer in acidic environment and adheres to the ulcer site, forming a barrier Give approximately 2 hours before or after drugs Take on an empty stomach before meals Chelated Bismuth Protects the ulcer crater and allows healing Some activity against H. pylori Should not be used repeatedly or for more than 2 months at a time Can cause black stools, constipation Helicobacter Pylori Usually passed from person to person through direct contact with saliva, vomit or stool or i may also be spread through contaminated food or water H. pylori are bacteria able to attach to the epithelial cells of the stomach and duodenum which stops them from being washed out of the stomach Once attached, the bacteria start to cause damage to the cells by secreting degradative enzymes, toxins and initiating a selfdestructive immune response www.science.org.au/ nobel/2005/images/invasion.jpg H. Pylori Treatment >85% PUD caused by H. pylori Antibiotic Ulcer Therapy - Used in Combinations Bismuth - Disrupts bacterial cell wall Clarithromycin - Inhibits protein systhesis Amoxicillin - Disrupts cell wall Tetracycline - Inhibits protein synthesis Metronidazone - Used often due to bacterial resistance to amoxicillin and tetracycline, or due to intolerance Triple Therapy – 14 days treatment - Effective 80-85% Proton pump inhibitor + amoxicillin/tetracycline + metronidazole/clarithromycin Quadruple Therapy - 10 days treatment, as efficacious as triple therapy - Add Bismuth to triple therapy