Gastrointestinal Drugs 0 Patrick T. Ronaldson, Ph.D. Department of Medical Pharmacology firstname.lastname@example.org
0 Topics for Discussion • Drugs for Acid-Peptic Disorders • Eradication of Helicobacter pylori(Antibiotic/Inhibition of Acid) • Proton Pump Inhibitors(Omeprazole) • Histamine (H2) Receptor Antagonists(Cimetidine, Ranitidine) • Anticholinergics • Prostaglandins(Misoprostol) • Antacids • Mucoprotective Drugs(Sucralfate) • Drugs for Motility Disorders • Prokinetics(Metoclopramide) • Laxatives(Bran) • Antidiarrheals(Opioids)
0 What is GERD? • Gastroesophageal Reflux Disease (GERD): GERD is when acid and pepsin from the stomach flows backward up into the esophagus often called heartburn; Approximately 10-20% of Americans experience GERD symptoms every day. - One of the most common medical conditions. - Source: El-Serag (2007). Clin Gastroent Hepatol. 5: 17-26.
0 What Causes GERD? 1) Overproduction of acid/pepsin 2) Over relaxation of the Lower Esophageal Sphincter (LES); Complications; if not treated - severe chest pains, bleeding or a pre-malignant change in the lining of the esophagus called Barrett’s esophagus – can result in adenocarcinoma
Barrett’s Esophagus • Demarcated by histological changes in cells lining the esophagus. • Occurs in 10% of GERD patients. • Incidence is 1% in the general population. • Associated with adenocarcinoma of the esophagus. Lower esophagus lined by red-coloured tissue, not the usual white-pink colour. Cameron. 2002. Diseases of the esophagus. 15: 106-108.
0 What is Peptic Ulcer Disease • Definition of Peptic Ulcer: A benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is exposed to acid and pepsin; 1) Excess acid production 2)Intrinsic defect in the mucosal defense barrier
0 Peptic Ulcer Disease 25 million Americans suffer from peptic ulcer disease Each year there are 500,000 to 850,000 new cases More than one million ulcer-related hospitalizations. Average size ¼ and ½ inch in diameter U.S. - duodenal ulcers are three times more common than gastric ulcers.
0 A Gastric Peptic Ulcer
0 Who Gets Peptic Ulcers • Peptic Ulcer Disease Affects All Age Groups • Can occur in children, although rare • Duodenal ulcers tends to occur first at around the age 25 and continue until the age of 75 • Gastric ulcers peak in people between the ages of 55 and 65 • Men Have Twice The Risk as Women Do • Genetic Factors • High levels of acid production, weakness in mucosal layer, abnormal nonprotective mucus production • Increase Acid Production and/or Decrease in Bicarbonate and PG Production • Caffeine, Cigarettes, Alcohol, Fruit Juices, Stress
What Causes Peptic Ulcer Disease • Helicobacter Pylori (H. pylori) • Most ulcers are the result of infection with H. pylori • Not all of those infected with H. pylori develop ulcers • H. pylori MAY result in a weakening of the mucosal defense systems, allowing for development of ulcer subsequent to acid/pepsin aggression;
What Causes Peptic Ulcer Disease • NSAIDs Long term use of nonsteroidal anti-inflammatory drugs. NSAIDs block COX enzymes and decrease prostaglandins (PGs). • Gastrinoma (Zollinger-Ellison Syndrome) Tumors of the duodenum or pancreas and secrete abnormally high amounts of gastrin which stimulates gastric acid. • Stress ulcers Result of physical trauma (i.e., burn patients).
Duodenal Ulcer Gastric Ulcer HP NSAID Cancer (ZE) Other Pathophysiological Processes Involved in Duodenal and Gastric Ulcers
Helicobacter pylori Spiral shaped, flagellated, Gram negative bacterium
H. pylori Adapted to an Acidic Environment • Primarily colonizes in the antrum of the stomach; • Resides mainly within the gastric mucus; • Has a high activity of the enzyme urease which enables it to colonize in the stomach.
Role of H. pylori in Peptic Ulcer Disease • Transmission: • Thought to be spread by fecal-oral route; • Possible ?oral-oral transmission?; • Infection thought to occur between parents and young children; • Additional Notes: • Correlated with socioeconomic status; • Almost universal infection in developing countries; • Most of those infected are asymptomatic.
Percentages of Population Infected with H. pylori www.helico.com
Role of H. pylori in Peptic Ulcer Disease • The host reaction to H. pylori determines the outcome of the infection: • Gastritis • GERD • Gastric & Duodenal Ulcers • Gastric Cancer (?)
Prevalence of H. pylori Infection in the U.S. HP- HP+ Duodenal ulcer Gastric ulcer Gastric lymphoma Gastric cancer
Role of H. pylori in Peptic Ulcer Disease • Diagnosis: • The majority cases of peptic ulcer disease are related to H. pylori. • The diagnosis of H. pylori infection must be confirmed prior to initiation of therapy (histology and culture, antibody test, urease CLO test)
Urease CLO test (PYtest) Cost of test $50-$100 www.helico.com
0 What Causes Peptic Ulcer Disease • Helicobacter Pylori • NSAIDs • Gastrinoma (Zollinger-Ellison Syndrome) • Stress ulcers
Cyclooxygenase Pathway Arachidonic Acid COX-1 Prostacycline Synthase Thromboxane Synthase Prostaglandin H2 Prostaglandin G2 Prostaglandin Synthase Prostacycline PG12 Thromboxane A2 Thromboxane B2 Prostacycline E2, F2 Prostacycline G2 RESULT = DECREASED ACID SECRETION & INCREASED MUCUS PRODUCTION
Neuroanatomy of the GI 0 Thalamus & Insula Hypothalamus & Amygdala Olfactory bulb Olfactory tract Olfactory epithelium Parabrachial nucleus
CNS Conditioned Reflexes: 1) Nucleus Tractus Solitarius (NTS); 2) Hypothalamus; 3) Dorsal Motor Nucleus of the Vagal Nerve (DMNV) Reflexes Include: Smell, Taste, Chewing, Swallowing & Hypoglycemia Vagal Nucleus 0 Ach Ach
Gastric lumen Mucus Superficial Epithelial Cells Found in the Mucous Neck Cells Body and Fundus of the Stomach Parietal Cells Peptic Cells (also known as Chief Cells) Muscularis Mucosa
Ach Ach H G G G G G G G G G G H 0 Acetylcholine, Gastrin and HistamineStimulate Parietal Cell Secretion of Acid Cholinergic Neuron Cholinergic Neuron Enterochromaffin- like Cell Antral G Cell Ach Ach Parietal Cell Acid Acid Circulation
CNS Conditioned Reflexes: 1) Nucleus Tractus Solitarius (NTS); 2) Hypothalamus; 3) Dorsal Motor Nucleus of the Vagal Nerve (DMNV) Reflexes Include: Smell, Taste, Chewing, Swallowing & Hypoglycemia Vagal Nucleus 0 Ach Parietal Cell Histamine H+ Ach G-cell Gastrin
Multiple Mechanisms Regulate Gastric Acid • Neural Acetylcholine • Hormonal Gastrin • Paracrine Histamine
Each Secretagogue Binds to its Own Receptor and Interacts with the Others CCK2 Gastrin Ca+2 dep. pathway H2 Histamine cAMP dep. pathway H+ PP Gastric Lumen M3 Ca+2 dep. pathway Acetylcholine
0 Strategies for Protecting the Gastric Mucosa from Acid Exposure Mechanisms Example Cimetidine Omeprazole Prostaglandins Muscarinic antagonists Inhibit secretion H+ Prevent contact H+ Sucralfate Neutralize acid Antacids H+
0 Strategies for Inhibiting Parietal Cell Acid Secretion CCK2 Gastrin Antagonists ↓ Ca+2 H2 Histamine Antagonists ↓cAMP H+ PP Gastric Lumen M3 Muscarinic Antagonists ↓ Ca+2
Strategies for Inhibiting Parietal Cell Acid Secretion Apical Basolateral cAMP H2 (+) Histamine (+) Protein Kinase • H+ PP K+ ATP (-) (-) EP3 cAMP PGI2 PGE2 Parietal Cell EP3 Mucus M? HCO3- Superficial Epithelial Cell pH 2 pH 6.7
Ca2+ Strategies for Inhibiting Parietal Cell Acid Secretion CCK2 Proton pump Inhibitors (-) EP3 cAMP Protein Kinase • H+ H2 PP (+) ATP M3 Ca2+
H+, K+-ATPase (the proton pump) is the final transport pathway for parietal cell hydrogen ion secretion • H+, K+-ATPase is located in the apical membrane of the oxyntic cell along the secretory canaliculi; • The pump requires large amounts of energy that is supplied by intracellular ATP; • Inhibition of H+, K+-ATPase blocks both basal and stimulated acid secretion.
Omeprazole (Prilosec) • Prototype H+, K+-ATPase inhibitor; A prodrug that needs a low pH to be active; • Irreversible (forms a covalent bond with the proton pump) - long lasting inhibition of acid production; • Profound reduction of gastric acid - elevates gastric pH significantly (20mg/day for 7days will decrease acid by 95%); • Highly protein bound; Metabolized by CYP2C & CYP3A; plasma half life of 1 to2 hours but long duration of action; Should be taken just prior to a meal and should NOT be taken with other acid-suppressing agents.
0 Esomeprazole (Nexium) Simply the S-isomer of omeprazole; H+, K+-ATPase inhibitor; Given orally. Rabeprazole (Aciphex)Lansoprazole (Prevecid) H+, K+-ATPase inhibitor; Given orally. Pantoprazole (Protonix) H+, K+-ATPase inhibitor; An acid-stable form and can be given by i.v.
0 Proton Pump Inhibitors (PPI) Well Tolerated Hypergastrinemia (can lead to tumor growth in the GI) Nausea Headaches, skin rashes
Ca2+ Strategies for Inhibiting Parietal Cell Acid Secretion CCK2 EP3 (-) cAMP H+ Protein Kinase Histamine Antagonist H2 PP K+ ATP M3 Ca2+
Histamine Receptors • H1 receptors • Smooth muscle • Nerves • H2 receptors • Parietal cells
Histamine H2 Antagonists Decrease Acid Output Histamine cAMP H+ Protein Kinase PP K+ ATP H2 antagonist administered orally at arrow Histamine Antagonist 30 20 Acid Output (mEq/hr) 10 Time (hr) 1 2 3 4 5
Histamine H2 Antagonists • Cimetidine (Tagamet) • Ranitidine (Zantac) • Famotidine (Pepcid) • Nizatidine (Axid)
Drugs for Acid-Peptic Disorders - Cimetidine (Tagamet) • Competitive H2 receptor Antagonist; • Markedly inhibits basal acid secretion including nocturnal secretion; • Readily absorbed after oral administration; • Relatively brief duration of action (4-8 hr) • Given on a multiple dosing schedule; • (300-400 mg, 2-4 times daily); • Typical therapy is for 4-8 weeks.
Drugs for Acid-Peptic Disorders - Cimetidine (Tagamet) • Side effects include inhibition of the microsomal metabolism of other drugs results in higher blood levels and enhancement of their effects • Interactions have been shown with: Diazepam Chlordiazepoxide Theophylline Phenytoin Warfarin Propranolol Meperidine Pentobarbital Lidocaine and many others...
Drugs for Acid-Peptic Disorders - Cimetidine (Tagamet) Additional Side effects: • In some patients, cimetidine acts as a nonsteroidal antiandrogen (i.e., interferes with estrogen metabolism). decrease in male sexual function gynecomastia (swelling of the breasts and soreness of the nipples in males) • Can produce confusion and disorientation in elderly patients; • Diarrhea, rash and miscellaneous other effects in a small number of patients.
Drugs for Acid-Peptic Disorders - Ranitidine (Zantac), Famotidine (pepcid), Nizatidine (Axid) • Same mechanism of action as Cimetidine but a longer duration of action (8 to 12 hrs); • Can be given less frequently; 150 or 300 mg, 1-2 times daily • Less interactions at P450 than Cimetidine.