Published on February 26, 2012
PowerPoint Presentation: 1 PROTON PUMP INHIBITORS Dr.J.SARAVANAN PowerPoint Presentation: 2 Anatomy of stomach . Brief introduction of peptic ulcer . History of proton pump inhibitors . Definition & introduction of proton pump inhibitors. Regulation of gastric acid secretion . Mechanism of gastric acid secretion . Inhibition of gastric acid secretion . Test assays for studying gastric acid inhibitors. STOMACH ANATOMY: 3 STOMACH ANATOMY The human stomach is a muscular, elastic, pear-shaped bag, lying crosswise in the abdominal cavity beneath the diaphragm. It changes size and shape according to the amount of food inside. PowerPoint Presentation: 4 The stomach is the portion of the digestive system most responsible for breaking down food. It has a saclike shape and is located between the esophagus and the intestines. Capacity of 1 liter or more. Functions:: 5 Functions : Acts as a storage tank for food. Site of food breakdown. Chemical breakdown of protein begins. Delivers chyme (processed food) to the small intestine. Regions:: 6 Regions: Cardiac region Fundic region Body region Pyloric region Structure of the Stomach Mucosa: 7 Structure of the Stomach Mucosa Gastric cell products: 8 Gastric cell products CELL TYPE PRODUCT Surface cells Neck cells Mucous,HCO 3 , Tefoil peptides Parietal cells HCl, Intrinsic factor Chief cells Pepsinogen, Gastric lipase Endocrine cells Gastrin, Histamine, Somatostatin Gastric juice (secretion): 9 COMPONENT FUNCTIONS Pepsinogen Inactive form of pepsin Pepsin Protein-splitting enzyme capabale of digesting nearly all types of proteins Hydrochloric acid Changes pepsinogen to pepsin; provides an acid environment needed for the action of pepsin Mucus Provides viscous , alkaline protective layer on the stomach wall Intrinsic factor Aids in the absorption of vit.B 12 . Gastric juice (secretion) PEPTIC ULCER: 10 PEPTIC ULCER Peptic ulcer is a sore in the inner lining of the stomach , small intestine (“duodenum”) OR “esophagus”. It occurs when the Stomach OR the small intestine’s inner layer is broken down by digestive juices (HCl & Pepsin). PowerPoint Presentation: 11 The most common causes are : A bacteria: Helicobacter pylori (H.pylori) Use of a group of drugs called NSAIDS : Aspirin , Aleve ,etc… PowerPoint Presentation: 12 H.pylori is a gram negative bacteria & is the most common infection of mankind. It is a spiral-shaped bacterium that lives in the acidic environment of the stomach. It is acquired by ingesting contaminated food OR water OR through person to person contact. If person carries this for 20-30 years it can lead to stomach cancer. Types of peptic ulcer: 13 Types of peptic ulcer Acute peptic ulcer Chronic peptic ulcer Acute peptic ulcer Also known as stress ulcers. These acute peptic ulcer are multiple, small mucosal erosions, seen mainly in the stomach and occasionally in the duodenum . 2. Chronic peptic ulcer If not specified CPU would mean gastric and duodenal ulcer .The two major forms of peptic ulcer disease of the upper GIT in which acid pepsin secretion are implicated in their pathogenesis. Duodenal Ulcers: 14 Duodenal Ulcers Duodenal sites are 4x as common as gastric sites. Most common in middle age . peak 30-50 years Male to female ratio— 4: 1 . Genetic link: 3x more common in 1 st degree relatives. More common in patients with blood group O. H. pylori infection common up to 95%. Smoking is twice as common. Gastric Ulcers: 15 Gastric Ulcers Common in late middle age. incidence increases with age Male to female ratio—2:1. More common in patients with blood group A . Use of NSAIDs - associated with a three- to four-fold increase in risk of gastric ulcer . Less related to H. pylori than duodenal ulcers – about 80%. PowerPoint Presentation: 16 HISTORY OF PROTON PUMP INHIBITORS: 17 HISTORY OF PROTON PUMP INHIBITORS In 1967 Ivan Östholm (Astra Hässle) started a project to develop a local anesthetic which is stable at acidic pH Fails because all local anaesthetics get protonated at acidic pH In 1973 the project was revived by another compound (CMN 131 from servier) Fails because of severe toxicity In 1973 H 77/76 was developed as a promising leading compound (synthesized to contain =S atom which is responsible for activity) Effective but not very potent PowerPoint Presentation: 18 In 1974 Timoprazole (H 124/26 ) was developed as a more promising leading compound Fails because it was included in a Hungerian patent as anti TB drug In the same year (H 83/69 ) was developed to replace the parent compound It is a metabolite of H 124/26 Fails because it induces thyroid enlargement In 1977 George Sachs & John Forte discovered the “ Proton pump ” PowerPoint Presentation: 19 In 1978 Picoprazole (H 149/94 ) was evaluated for toxicity in animals However, it produced necrotizing vasculitis In 1979 Omeprazole (H 168/68 ) was found effective & non toxic in animals In 1982 the first published clinical study with the first PPI: Omeprazole DEFINITION: 20 DEFINITION proton-pump inhibitor (proh-ton-pump) n. a drug that reduces gastric acid secretion by blocking an enzyme (the proton pump ) within the oxyntic (parietal) cells of the gastric glands. (OR) Proton pump inhibitors (PPIs) are a class of compounds that block the acid secretion from parietal cells in the stomach, thereby providing relief from acid-related disorders . INTRODUCTION: 21 INTRODUCTION Proton pump inhibitors act by irreversibly blocking the hydrogen / potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase , or, more common, gastric proton pump ) of the gastric parietal cell . Gastric acid secretion is a useful therapeutic principle for the treatment of ulcer of the upper GIT. PowerPoint Presentation: 22 Proton pump inhibitors promote healing of ulcers in a greater percentage of people in a shorter period of time than do histamine-2 (H2) blockers like –ranitidine, famotidine . They are also very useful in treating conditions that cause excessive stomach acid secretion, such as Zollinger-Ellison syndrome & gastroesophageal reflux disease (GERD). PowerPoint Presentation: 23 Chemistry: a substituted benzimidazole (Previcid) (Prilosec) (Protonix) (Aciphex) Pharmacokinetics: 24 Pharmacokinetics They are prodrugs – taken orally. They are given as enteric coated capsules – to protect them from destruction by acidity in gastric lumen . They are rapidly absorbed from the intestine. They are activated in the acidic medium of the secretory parietal cell canaliculus . Inactivated if at neutral pH (combined with H 2 antagonists). PowerPoint Presentation: 25 . Have plasma half life of 1.5 h . Long duration of action (> 12 h-24 h). Once daily dose is sufficient . Given 1 h before meal. Bioavailability is reduced by food (50%). Are metabolized in the liver by CytP450. They are more potent than H 2 anatgonists. Pharmacodynamics: : 26 Pharmacodynamics: Block the last step in the secretion of gastric acid by combining with hydrogen , potassium, and adenosine triphosphate in the parietal cells of the stomach. PowerPoint Presentation: 27 . USES 1. Zollinger -Ellison syndrome (First choice). 2. Resistant severe peptic ulcer ( 4-8 weeks). 3. Reflux esophagitis. 4. prevention of bleeding from stress -related gastritis . 5. Eradication of H. pylori. Adverse reactions : Abdominal pain, diarrhea, nausea, and vomiting. GASTRIC ACID SECRETION: 28 GASTRIC ACID SECRETION Gastric acid is produced by parietal cells (also called oxyntic cells) in the stomach. Its secretion is a complex and relatively energetically expensive process. Parietal cells contain an extensive secretory network (called canaliculi ) from which the gastric acid is secreted into the lumen of the stomach. These cells are part of epithelial fundic glands in the gastric mucosa . The pH of gastric acid is 2 to 3 in the human stomach lumen, the acidity being maintained by the proton pump H+/K+ ATPase . : 29 Gastric acid secretion appears in the fundic region of the stomach. The oxyntic gland represents the secretory unit of the fundic mucosa. The acid secreting parietal cells are located in the wall of its midsection. In addition to parietal cells the gland consist of pepsinogen secreting chief cells, mucous secreting mucous cells, neck cells, endocrine, and somatostatin cells. MECHANISM OF ACID SECRETION: 30 MECHANISM OF ACID SECRETION PowerPoint Presentation: 31 Acetylcholine originates in the vagus nerves. Gastrin is synthesized and stored in the antral G-cell of the stomach and its secretion into the blood is stimulated by amino acid in the gastric juice. Histamine is released by mast cells or mast cell like cells of the gastric mucosa. The histamine receptor on the parietal cell belong to the H 2 receptor subclass. The binding of Acetylcholine or gastrin to their specific receptors increases intracellular calcium. PowerPoint Presentation: 32 The binding of histamine to its H 2 receptor on the parietal cell activates the membrane bounded adenylate cyclase with a corresponding increase in intracellular cyclic AMP levels. Increase level of both intracellular calcium and cyclic AMP finally cause acid secretion PowerPoint Presentation: 33 The key player in acid secretion is a H+/K+ ATPase or " proton pump " located in the cannalicular membrane. This ATPase is magnesium-dependent, and not inhibitable by ouabain. The current model for explaining acid secretion is as follows : Hydrogen ions are generated within the parietal cell from dissociation of water. The hydroxyl ions formed in this process rapidly combine with carbon dioxide to form bicarbonate ion, a reaction cataylzed by carbonic anhydrase . Bicarbonate is transported out of the basolateral membrane in exchange for chloride. The outflow of bicarbonate into blood results in a slight elevation of blood pH known as the "alkaline tide". This process serves to maintain intracellular pH in the parietal cell. PowerPoint Presentation: 34 3. Chloride and potassium ions are transported into the lumen of the cannaliculus by conductance channels, and such is necessary for secretion of acid 4. Hydrogen ion is pumped out of the cell, into the lumen, in exchange for potassium through the action of the proton pump; potassium is thus effectively recycled. 5.Accumulation of osmotically-active hydrogen ion in the cannaliculus generates an osmotic gradient across the membrane that results in outward diffusion of water - the resulting gastric juice is 155 mM HCl and 15 mM KCl with a small amount of NaCl. These processes are depicted in the animation below. Animation: 35 Animation INHIBITION OF GASTRIC ACID SECRETION: 36 INHIBITION OF GASTRIC ACID SECRETION Gastric acid secretion can be inhibited pharmacologically by By specific antagonists of the stimulatory receptors ( muscarinic – M 1 / M 2 , gastrin,histamine -H 2 ) By agonists to inhibitory receptor ( prostaglandin, somatostatin) By carbonic anhydrous inhibitors ( acetazolamide, ethoxazolamide) Proton pump inhibitor- omeprazole, lansoprazole . The inhibitory profiles of gastric acid inhibitors with different mode of action: 37 The inhibitory profiles of gastric acid inhibitors with different mode of action Inhibitor Stimulant Carbachol Gastrin Histamine Forskoline /IBMX intracellular Receptor level Atropine + - - - Proglumide - + - - Cimetidine - + + - Omeprazole + + + + PowerPoint Presentation: 38 stomach lumen perfused rat model: Acid secretion initial injection of isobutyl methylxanthine followed by an infusion of forskoline. Only the PPI (Omeprazole) can also inhibit the IBMX-forskoline induced gastric acid secretion whereas the others can not inhibit it. TEST ASSAYS FOR STUDYING GASTRIC ACID INHIBITORS: 39 TEST ASSAYS FOR STUDYING GASTRIC ACID INHIBITORS The biochemical characterization of a compound for its inhibitory effectiveness on gastric acid secretion requires in vivo studies in laboratory animals in vitro studies in isolated stomach, fundic mucosa, gastric gland cells and sub cellular fractions (enzymes & receptors). in vitro studies -- mechanism of action of any compound of interest. in vivo (animal) studies -- compound’s practical usefulness . PowerPoint Presentation: 40 A compound active in vitro must fulfill all of the bellow mentioned criteria for practical usefulness in animal studies : The compound should be stable enough to pass through the aggressive environment of the gastric juice (chemical stability) or to get absorbed by the stomach wall in its active form . The compound should be absorbed from the gut so as to become systemically available (bioavailability). PowerPoint Presentation: 41 Then the compound should be distributed in the body to reach the target organ and should be present at the target organ for a sufficient length of time to exert the desired pharmacological effect. Afterwards it should be eliminated as completely as possible either in its original form or following metabolism. IN VIVO STUDY : 42 IN VIVO STUDY Gastric acid secretion can be studied in vivo in rats and dogs. Conscious rat models: rats ( chronic gastric fistula) anesthetized with stomach-lumen perfusion . Gastric acid secretion can be studied under - basal condition as well as - during stimulation of gastric acid secretion following on iv infusion or subcutaneous injection of a secretagogue i.e., carbachol, gastrin or histamine PowerPoint Presentation: 43 Gastric acid secretion can be studied in a -DOG ( chronic gastric fistula or with a heidenhain pouch.) This is most commonly done during stimulatory conditions, e.g., a continuous IV infusion with histamine . As the heidenhain pouch is vagally denervated . PowerPoint Presentation: 44 Several prostaglandins CYTOPROTECTION (rat) no antisecretory activity. However, clinical experience with prostaglandins has shown that ulcer healing is only achieved at antisecretory doses. Therefore , it seems very likely that the cytoprotective property of a compound in rats has very limited ulcer healing potential in humans. If cytoprotection is really separated from the antisecretory potential. causes IN VITRO STUDY : 45 IN VITRO STUDY The effect of gastric proton pump inhibitors on H + /K + ATPase activity (ATP cleavage) can be studied in vitro with partially purified H + /K + ATPase preparations. Enzyme assay should be performed at neutral P H values and since proton pump inhibitors of the omeprazole type need acid activation ( In acidic environments, protonation of the pyridine and benzimidazole nitrogens result in formation of a tetracycline sulfenamide which is the active form of the drug. . PowerPoint Presentation: 46 Acid formation in vitro has been studied in isolated parietal cells from guinea pigs, dogs, and rabbits as well as whole gastric glands from rabbits and humans. Measurement of acid formation is achieved indirectly by means of the weak base 14 C aminopyrine (P ka 5.0), within the secretary compartment of the parietal cell. Due to its weak basic nature 14 C aminopyrine accumulate in acidic compartments. At the P H 7.4 it can pass freely through biological membranes in its unionized form but become trapped immediately within the secretary canaliculi because of ionization. PowerPoint Presentation: 47 Furthermore oxygen consumption correlates with acid formation and has been very useful to identify artifacts of inhibition of 14C aminopyrine accumulation through neutralization of the acidic compartment by the basic nature of the compound . This has been widely used to study - SAR of gastric acid inhibitors as well as - to separate the inhibitory effect of the PPI from that of receptor antagonists. Histamine H 2 receptor antagonists act only during histamine stimulation but cause no inhibitory effect in case of AMP stimulated 14C aminopyrine uptake. But proton pump inhibitor inhibits both kind of stimulation QUESTIONS: 48 QUESTIONS Proton pump inhibitors?(10M) What is meant by gastric proton pump inhibitor? Discuss the development of gastric proton pump inhibitor. Write a note on studying their test assay?(20M) Discuss the design of a gastric proton pump inhibitor. Add a note on gastric acid secretion and their inhibition?**(20M) Discuss the test assays for studying gastric acid inhibitors?(10M)** Discuss the development of proton pump inhibitor and add a note on studying their test assay?(13M) PowerPoint Presentation: 49 6. Describe with examples , chemistry and mode of action of gastric proton pump inhibitors?(12M) 7. What are gastric proton pump inhibitors? Discuss the design of PPI’S with examples and describe the mode of action of Omeprazole?(12M) 8. What is the importance of GPPI’S ? Discuss the design of GPPI’S with examples?(12M) 9. Gastric acid secretion and inhibition?(13M) REFERENCES: 50 REFERENCES Burger’s Medicinal Chemistry and Drug Discovery, fifth edition, volume-1. Wilson & Giswold’s Medicinal Chemistry. Pharmacology by Tripati . Internet.