Gastrointestinal Pharmacology
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1 Gastrointestinal Pharmacology Jan Kehr Department of Physiology and Pharmacology
2 Gastrointestinal Pharmacology v Background v Peptic disorders v Constipation and Diarrhea v Chronic Bowel Disease Gastrointestinal Pharmacology April 16 2
3 The enteric nervous system (ENS) I v The autonomic nervous system has 3 divisions: ü sympathetic ü parasympathetic ü enteric v The enteric nervous system: ü located in the GI tissue, but can be modified by input from the brain ü a collection of nerve plexuses that surround the GI tract ü contain over 100 million neurons ü contain many different neurotransmitters (e.g. ACh, DA, NA, 5-HT) and neuromodulators v The ENS regulates: ü rythmic contraction of intestinal smooth muscle ü secretory functions of intestinal epithelial cells Gastrointestinal Pharmacology April 16 3
4 The enteric nervous system (ENS) II v Neurons of the ENS clustered into: ü ü The submucosal plexus (Meisner s plexus) o regulating GI blood flow and epithelial cell function The myenteric plexus (Auerbach s plexus) o Control digestive tract motility v The nerve plexuses consist of: ü Sensory neurons recieve information from sensory receptors (mechanical, thermal, osmotic, chemical stimuli) in the mucosa and the muscles - information on gut contents and the state of the GI wall. ü ü Motor neurons affect smooth muscle cells and gland in the GI tract and control GI motility, secretion, and absorbtion Interneurons largely responsible for integrating information from sensory neurons and providing it to ("programming") enteric motor neurons Gastrointestinal Pharmacology April 16 4
5 Innervations of the of GI tract The ENS can and does function autonomously - but normal digestive function requires CNS communication. v Parasympathetic innervation of the GI tract ü vagus nerve stimulation (pharynx distal colon) ü ACh ü stimulates: GI secretion, motor activity and contraction of GI sphincters v Sympathetic innervation of the GI tract: ü postganglionic neurons ü NA ü inhibits: GI secretion, motor activity and contraction of GI sphincters v Bidirecttional communication: GI higher CNS centers Gastrointestinal Pharmacology April 16 5
6 GI hormones Gastrointestinal Pharmacology April 16 6
7 The Gastric pit Gastrointestinal Pharmacology April 16 7
8 Gastric acid I v The best known component of gastric juice is HCl v Parietal cells v L gastric juice per day v Highly acidic environment v Activates pepsinogen to pepsin (degradation of proteins) v Inhibition of growth of microorganisms v Control of acid secretion: ü Acetylcholine ü Histamine (H 2 receptors) ü Gastrin Gastrointestinal Pharmacology April 16 8
9 Gastric acid II q Gastrin hormonal regulation q ACh nervous regulation q Histamine released after hormonal and nervous regulation Gastrointestinal Pharmacology April 16 9
10 Mechanism of acid secretion H + is generated from the dissocation of water 2. The OH - from this reaction is catalyzed to HCO 3-3. HCO 3 - is transported out of the cell in exchange of Cl - 4. Cl - and K + transported into the lumen by conductance channels 5. H + is pumped out of the cell in exchange of K + - K + is effectively recycled by the proton pump Gastrointestinal Pharmacology April 16 10
11 PEPTIC DISORDERS Gastrointestinal Pharmacology April 16 11
12 Peptic disorders v Gastroesophageal reflux disease (GERD) v Gastritis v Ulcus Gastrointestinal Pharmacology April 16 12
13 Gastroesophageal reflux disease (GERD) GERD occurs when the lower esophageal sphincter (LES) opens spontaneously, for varying periods of time, or does not close properly and stomach contents rise up into the esophagus. Gastrointestinal Pharmacology April 16 13
14 Gastroesophageal reflux disease (GERD) GERD occurs when the lower esophageal sphincter (LES) opens spontaneously, for varying periods of time, or does not close properly and stomach contents rise up into the esophagus. v Persistent reflux that occurs more than twice a week is considered GERD, and it can eventually lead to more serious health problems. v Symptoms ü Heartburn (acid indigestion-burning pain) ü Regurgitation ü Dry cough ü Asthma symptoms ü Trouble swallowing Gastrointestinal Pharmacology April 16 14
15 Gastritis I v Inflammation of the stomach lining. Gastrointestinal Pharmacology April 16 15
16 Gastritis II v Inflammation of the stomach lining. v Causes ü Infections most common: Helicobacter pylori ü Injury ü Drugs - especially aspirin and other nonsteroidal anti-inflammatory drugs ü Disorders of the immune system v Gastritis usually causes no symptoms. v Gastritis can lead to ulcers, which may cause the symptoms to get worse Gastrointestinal Pharmacology April 16 16
17 Ulcus I v A peptic ulcer is a round or oval sore where the lining of the stomach or duodenum has been eaten away by stomach acid and digestive juices. Gastrointestinal Pharmacology April 16 17
18 Ulcus II v A peptic ulcer is a round or oval sore where the lining of the stomach or duodenum has been eaten away by stomach acid and digestive juices. v Peptic ulcers can result from an infection with Helicobacter pylori or from drugs that weaken the lining of the stomach or duodenum. Symptoms v Gnawing, burning, aching, soreness, an empty feeling, and hunger - The pain is steady and mild or moderately severe and usually located just below the breastbone. v Bleeding - morbidity and mortality Gastrointestinal Pharmacology April 16 18
19 Helicobacter Pylori The Nobel Prize in Physiology or Medicine 2005 was awarded jointly to Barry J. Marshall and J. Robin Warren "for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease" Gastrointestinal Pharmacology April 16 19
20 Helicobacter Pylori II v The most common infection in the world 60-90% of the the world s population has been estimated to be infected v Gastritis: %, ulcers: 70-80% v May cause of chronic gastritis and is associated with duodenal ulcer disease, gastric ulcer disease, and gastric cancer v Gramnegative, gastric bacterium with a bundle of flagellas v Produces urease enables the organism to survive in the acidic stomach by creating an alkaline environment v Biopsy positive culture, serologic tests or urea breath tests Gastrointestinal Pharmacology April 16 20
21 Helicobacter Pylori III 1. H. pylori penetrates the mucus layer of the stomach and adheres to the surface of gastric mucosal epithelial cells. 2. Ammonia is produced which neutralizes the gastric acid 3. The H. Pylori proliferates, and migrates, and finally causes inflammation. 4. Gastric ulcerization (or peptic ulcers) is developed by the destruction of the mucosa, inflammation and mucosal cell death Gastrointestinal Pharmacology April 16 21
22 Treatment strategy v Lifestyle changes ü Diet ü Weight loss ü Smoking and Alcohol habits v Pharmacological strategies: 1. Neutrilize secreted acid 2. Decrease the secretion of gastric acid 3. Protect the mucosa 4. Attack the Helicobacter Pylori infection Gastrointestinal Pharmacology April 16 22
23 1. Antacids Antacids (alkalines) perform a neutralization reaction: - increasing the ph to reduce acidity in the stomach - inhibiting the activity of peptic enzymes Examples of antacids: v Magnesium Hydroxide ü forms MgCl 2 in the stomach v Magnesium Trisilicate ü forms MgCl 2 colloidal silica in the stomach v Aluminium Hydroxide gel ü forms AlCl in the stomach v Side effects (Novaluzid ): ü belching ü nausea ü flatulence Gastrointestinal Pharmacology April 16 23
24 2A. Histamine H 2 receptor antagonists v Examples: ü Ranitidin (Stomacid ) ü Famotidin (Pepsin ) v Inhibits: Histamine-, gastrin- and ACh-stimulated secretion v Side effects: ü Diarrhoea ü Dizziness ü Muscle pain ü Alopecia Gastrointestinal Pharmacology April 16 24
25 2B. Protonpump inhibitors v Inhibits the H + /K + ATPase pump irreversibly v Examples: v Omeprazole (Losec ) - prodrug v Esopremazole (Nexium ) v Side effects ü Diarrhea ü Dizziness ü Mental confusion ü Somnolence Gastrointestinal Pharmacology April 16 25
26 3A. Cytoprotective drugs I v Enhance the endodgenous mucosal protection mechanism and/or provide a physical barrier over the surface of the ulcer v Sucralfate (Andapsin ) ü a complex of the disaccharide sugar, sucrose, combined with sulfate and aluminum releases aluminum in the presence of acid ü the complex carries a strong negative charge binds to exposed proteins to the surface of the ulcer ü coats the ulcer complex gel with mucus ü inhibits pepsin ü may increase prostaglandin production v Side effects: ü most common constipation ü may reduce effectiveness of other drugs Gastrointestinal Pharmacology April 16 26
27 3B. Cytoprotective drugs II - Prostaglandine analogues v Examples: Misoprostol (Cytotec ) v Reduce gastric acid secretion v Cytoprotective by increasing: ü the mucosa layer ü the secretion of bicarbonate ü local blood flow ü the cell regeneration v Side effects ü Diarrhea ü Dysregulated menstruation ü Teratogenic Gastrointestinal Pharmacology April 16 27
28 4. Treatment of Helicopbacter pylori v Triple therapies: Proton pump inhibitor in combination antibiotics v Examples of antibiotics: ü Amoxelline (Amimox ) ü Clarithromycin (Klacid ) ü Metrondiazole (Flagyl ) v Triple therapies: ü omeprazole 40 mg x 1, amoxicilline 500 mg x 3, metronidazol 400 mg x 3 for one week ü omeprazole 20 mg x 2, clarithromycin 250 mg x 2, metronidazole 400 mg x 2 for one week ü omeprazole 20 mg x 2, clarithromycin 500 mg x 2, amoxicilline 1 g x 2 for one week Side effects: ü Metrondiazole metallic taste ü Clarithromycin nausea, diarrhoea, abdominal cramps ü Amoxelline - nausea, diarrhoea, abdominal cramps Gastrointestinal Pharmacology April 16 28
29 DRUGS USED IN CONSTIPATION AND DIARRHEA Gastrointestinal Pharmacology April 16 29
30 Constipation v infrequent stools v hard stools v difficulty passing stools v a sense of incomplete emptying after a bowel movement Drugs that alter the motility of the GI tract may help: v Purgatives accelerate the passage of food through the intestine v Agents that increase the motility of the GI smooth muscle without causing purgation Gastrointestinal Pharmacology April 16 30
31 Purgatives/Laxatives I 1. Laxatives 2. Faecal softeners 3. Stimulant purgatives 1. Bulk laxatives v include methylcellulose and extracts (e.g. agar, bran) v non-absorbable, non-breakable polysaccharide polymers forming a hydrated mass in the gut lumen v promotes peristalsis and improving faecal consistency v They may take several days to work but have no serious side effects Gastrointestinal Pharmacology April 16 31
32 Purgatives/Laxatives II 2. Faecal softners v Mineral oil: non-absorbable - make the intestinal walls and stool moist and slippery, thus facilitating defecation v Detergents : produces softer faeces 3. Stimulant laxatives v increases electrolyte and hence water secretion v stimulating the enteric nerves increasing peristalsis v side effects: abdominal cramping Gastrointestinal Pharmacology April 16 32
33 Diarrhea v Numeral causes: ü underlying disease ü Infections o Bacterias: secret toxins mucosal cells can not absorb H 2 O and NaCl o Viruses: cause inflammation of the GI wall increased fluid secretion and increast peristalsis ü Toxins ü Anxiety ü Side effects of drug or radial therapy In developing countries, acute diarrhea is one of the principal causes of death of malnourished infants Gastrointestinal Pharmacology April 16 33
34 Treatment strategy - diarreha v Treatment of severe acute diarrhea 1. Maintenance of fluid and electrolyte balance ü NaCl and glucose (Resorb ) 2. Use of anti-infective agents ü Antibiotics 3. Use of spasmolytic or other antidiarrheal agents ü Adsorbents (e.g. charcoal) binds toxins inactivation and elimination ü Opioids activates µ-receptors in the enteric nerve plexus ü Loperamide (Immodium ) opioid do not pass the BBB Side effects opioids: ü Constipation ü Abdominal cramps ü Drowsiness Gastrointestinal Pharmacology April 16 34
35 CHRONIC BOWEL DISEASES Gastrointestinal Pharmacology April 16 35
36 Chronic bowel diseases 1. Irritable bowel disease 2. Ulcerative colitis 3. Crohn s disease Gastrointestinal Pharmacology April 16 36
37 Crohn s disease Chronic inflammatory disease of the intestines. It primarily causes ulcerations (breaks in the lining) of the small and large intestines, but can affect the digestive system anywhere from the mouth to the anus Symptoms v Chronic diarrhea (blood and mucous) v Weight loss v Rectal bleeding v Fever v Night sweats Gastrointestinal Pharmacology April 16 37
38 Crohn s disease - treatment There is no medication that can cure Crohn's disease focus on alleviating the symptoms of the patient. v Anti-inflammatory agents: 5- ASA compounds and glucocorticoids v Topical antibiotics v Immuno-modulators Gastrointestinal Pharmacology April 16 38
39 Anti-inflammatory agents Sulfasalzaline (Salazopurin ) is also used in RA v A chemical combination of sulfapyridin and 5-aminosalicylic acid (5-ASA) ü Prevents the absorption by the stomach v 5-ASA (mesalazine) bacterial activation in colon v 5-ASA may reduce inflammation by: ü Scavenging free radicals ü Inhibiting : o prostaglandin production o leukotriene production o neutrophil chemotaxis v Side effects: Diarrhea, salicylate sensitivity Gastrointestinal Pharmacology April 16 39
40 Immuno-modulators Azathioprine (Azatriopin ) v Metabolized to mercaptopurine v Both cell-mediated and antibody-mediated immune reactions are depressed by Azathioprine v Inhibits the clonal proliferation during the induction phase of the immune response by a cytotoxic action on dividing cells v Side effects: ü Depression of the bone marrow ü Nausea ü Vomiting ü Skin eruptions ü Mild hepatotoxicity Gastrointestinal Pharmacology April 16 40
41 Summary I Peptic Ulcers Pharmacological strategies: ü Neutrilize secreted acid - Antacids ü Decrease the secretion of gastric acid proton pump inhibitors, H 2 receptor antagonists ü Protect the mucousa Cytoprotective drugs ü Attack the Helicobacter Pylori infection Antibiotics Constipation ü Purgatives ü Laxatives Gastrointestinal Pharmacology April 16 41
42 Summary II Diarrhea Pharmacological strategies: ü Maintenance of fluid and electrolyte balance NaCl and glucose ü Use of anti-infective agents - Antibiotics ü Use of spasmolytic or other antidiarrheal agents- Adsorbents, Opioids Chronic Bowel Diseases ü Surgery Pharmacological strategies: ü Anti-inflammatory agents ü Immunomodulaters Gastrointestinal Pharmacology April 16 42
43 Gastrointestinal Pharmacology April 16 43
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