GIT pharmacology .ppt

GIT PHARMACOLOGY G.O. AFOLAYAN Ph.D  Peptic Ulcer  A peptic ulcer (stomach or duodenal) is a break in the inner lining of the esophagus, stomach, or duodenum. A peptic ulcer of the stomach is called a gastric ulcer; of the duodenum, a duodenal ulcer; and of...

GIT PHARMACOLOGY G.O. AFOLAYAN Ph.D  Peptic Ulcer  A peptic ulcer (stomach or duodenal) is a break in the inner lining of the esophagus, stomach, or duodenum. A peptic ulcer of the stomach is called a gastric ulcer; of the duodenum, a duodenal ulcer; and of the esophagus, an esophageal ulcer.  The two most important initiating causes of ulcers are infection of the stomach by a bacterium named "Helicobacter pylori" (H. pylori) and chronic use of nonsteroidal anti- inflammatory medications (NSAIDs), e.g. aspirin.  Gastric Defenses Against Acid 1- Esophageal defense: the lower esophageal sphincter, which prevents reflux of acidic gastric contents into the esophagus. 2- Stomach defense: require adequate mucosal blood flow because of the high metabolic activity and oxygen requirements of the gastric mucosa a) Secretion of a mucus layer that protects gastric epithelial cells. Mucus production is stimulated by prostaglandins E2 and I2, which also directly inhibit gastric acid secretion by parietal cells. Drugs that inhibit prostaglandin formation (are alcohol and NSAIDs) decrease mucus secretion and predispose to the development of acid-peptic disease. b) Secretion of bicarbonate ions by superficial gastric epithelial cells. Bicarbonate neutralizes HCl.  Regulatory molecules that stimulate acid secretion Acetylcholine Produced from nerve endings and stimulate M3 receptor on: 1.Parietal cells (produce HCl) 2.Enterochromaffin cells and Mast cells (produce histamine) 3.G cells (produce gastrin) Histamine Produced by enterochromaffin cells and Mast cells in response to stimulation of M3 receptors (by acetylcholine) and CCK3 receptors by gastrin. It stimulates parietal cells to produce HCL Gastrin Produced by G cells in response to stimulation of M3 receptors by acetylcholine and stretch and by chemical substances in food Types of gastric HCl secretion 1- Nocturnal (basal) acid secretion: depend on histamine 2- Meal stimulated acid secretion: stimulated by: 1. Gastrin 2. Acetylcholine 3. Histamine Phases of gastric secretion 1)Cephalic Phase 2)Gastric Phase 3)Intestinal Phase  Phases of gastric secretion Phase Stimuli Pathway Cephalic Sight, smell, taste 1) Vagus (M3 receptors) (stimulate) or thought of food 2) Histamine (H2 receptor) 3) Gastrin Gastric (stimulate) Food in the 1) Stretch: local reflex (M3 stomach receptors) 2) Chemical substances in food (gastrin) 3) Increase pH: Inhibition of somatostatin release Intestinal (inhibit) Chyme in the duodenum Mechanism of HCl secretion Steps of gastric acid secretion by parietal cells  Management I- Agents that reduce gastric acidity 1. Proton pump inhibitors 2. H2 receptor antagonists 3. Muscarine receptor antagonists 4. Antacids II- Mucosal protective agents - Sucralfate - Prostaglandin (PGE1) agonists (misoprostol) - Colloidal bismuth compounds - Carbenoxolone I- Agents that reduce gastric acidity 1.Proton pump inhibitors 2.H2 receptor antagonists 3.Muscarine receptor antagonists 4.Antacids ACh PGE1 Histamine Gastrin M3 _ Adenyl H2 cyclase + Gastrin + PGE + receptor receptor ++ ATP cAMP Ca ++ Ca + + + Protein Kinase )Activated( + K+ + H Parietal cell Proton pump Lumen of stomach Gastric ACh PGE1 Histamine Gastrin M3 _ Adenyl H2 PGE cyclase + Gastrin receptor + + receptor ++ ATP cAMP Ca ++ Ca + + + Protein Kinase )Activated( + + K +K H Parietal cell Proton pump Lumen of stomach Gastric I- Agents that reduce increased gastric acidity 1- Proton pump inhibitors Proton pump inhibitors are the most potent suppressors of gastric acid secretion 1. Omeprazole 2. Esomeprazole 3. Lansoprazole 4. Rabeprazole 5.Pantoprazole Action: Inhibit both fasting (basal) and meal- stimulated HCl secretion by irreversible inactivation of the proton pump in the wall of parietal cells  Proton pump inhibitors Pharmacokinetics: Proton pump inhibitors are prodrugs that require activation in the acidic secretory canaliculi of parietal cells, where its converted to its active form: SULFENIC ACID. 1- Oral forms are prepared as acid resistant formulations that release the drug in the intestine (because they are degraded in acid media) 2- After absorption, they are distributed by blood to parietal cells 3-They irreversibly inactivate the proton pump molecule (providing 24- to 48-hour suppression of acid secretion, despite the much shorter plasma half-lives of the parent compounds).  Proton pump inhibitors Pharmacokinetics 4- they should be given on an empty stomach because food affects absorption 5- They should be given 30 minutes to 1 hour before food intake because an acidic pH in the parietal cell acid canaliculi is required for drug activation, and food stimulates acid production (Concomitant use of other drugs that inhibit acid secretion, such as H2-receptor antagonists, might be predicted to lessen the effectiveness of the proton pump inhibitors )  Proton pump inhibitors Pharmacokinetics 6- Maximal effect is reached after 3 to 4 days of administration (the time required to fully inactivate the proton pumps) 7- Their effects persists for 3 to 4 days after stopping the drug (the time required for the synthesis of new proton pumps molecules) 8- Metabolized by the liver (dose reduction is necessary in severe liver impairment) 9- Minimal excretion by the kidney ( no dose reduction is necessary in renal impairment)  Proton pump inhibitors Adverse effects Few 1- The most common are GIT troubles in the form of nausea, abdominal pain, constipation, flatulence, and diarrhea 2- Subacute myopathy, arthralgias, headaches, and skin rashes 3- Prolonged use leads to vitamin B12 deficiency (because HCl is important for releasing vitamin B12 from food). 4-Hypergastrinemia which may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy and may promote the growth of gastrointestinal tumors (carcinoid tumors )  Proton pump inhibitors Drug interactions Metabolized by cytochrome P450 enzymes (CYP2C19 and 3A4) and may interfere with the metabolism of drugs metabolized with cytochrome P450 such as warfarin, diazepam and cyclosporine increasing their levels and producing toxicity  Proton pump inhibitors Therapeutic uses 1. Gastroesophageal reflux disease (GERD) 2. Gastric and duodenal ulcers 3. Prevention of recurrence of non-steroidal anti-inflammatory drug (NSAID)-associated gastric ulcers in patients who continue NSAID use. 4. Reducing the risk of duodenal ulcer recurrence associated with H. pylori infections.  H2 receptor antagonists - Elimination Ranitidine Famotidine Nizatidine Small amounts are metabolized by the liver (liver disease is not an indication for adjusting dose) Drug and metabolites are excreted by the kidney (dose should be reduced in kidney disease) Mechanism of Suppression of HCl by competitive inhibition (i.e. reversibly action binding to) of H2 receptors in parietal cells. less potent than proton pump inhibitors They suppress basal gastric acid secretion more than meal stimulated secretion Uses 1- Gastroeophageal reflux disease (uncomplicated) 2- Gastric and duodenal ulcers 3- Prevention of occurrence of stress ulcers Adverse Few effects 1- GIT: diarrhea and constipation. 2- Headache, dizziness and fatigue and muscle pain 3- Hypergastrinemia Drug Agents that decrease gastric acidity alter the rate of interactions absorption and subsequent bioavailability of H2- receptor antagonists  Muscarine receptor antagonists 1. Pirenzepine 2. Telenzepine Mechanism of action: reduce meal stimulated HCl secretion by reversible blockade of muscarinic (M3) receptors on the cell bodies of the intramural cholinergic ganglia ( receptors on parietal cells are M3). Adverse effects: They produce anticholinergic side effects at doses that block HCl secretion Because of poor efficacy, side effects and delay of gastric emptying, they are not used in treating acid peptic disease I- Agents that reduce increased gastric acidity Antacids -4 :Mechanism of action Reduction of intragastric acidity by reacting with -1 gastric HCl to form salt and water Stimulate mucosal PG production -2 :Types NaHCO3 1- Sodium bicarbonate CaCO3 2- Calcium carbonate 3- Al hydroxide Al(OH) 3 Mg(OH)2 4- Magnesium hydroxide Chemical reactions of antacids with HCl in the stomach  Sodium Calcium Mg Aluminum bicarbonate carbonate hydroxide hydroxide Reaction Reacts rapidly Reacts slowly Reacts Reacts with HCl slowly slowly Products of NaCl and CO2 CaCl2 and CO2 MgCl2 and AlCl2 and the which produces which produces H2O H2O reaction gastric distension gastric and aggrevate distension hypertension Effect of absorbed causing alkalosis if given Unabsorbe Unabsorbe unreacted in high doses or in patients with d causing d causing antacids renal insufficiency osmotic constipatio diarrhoea n Precaution Affect absorption of other drugs therefore should not be given s within 2 hours of tetracycline or iron  Mucosal protective agents 1- Sucralfate Sucralfate = complex aluminum hydroxide + sulfate + sucrose Mechanism of action: 1- in acidic environment of the stomach, it forms a viscous paste that binds to ulcers or erosions for 6 hours forming a physical barrier against hydrolysis of mucosal proteins by pepsin. 2- stimulates mucosal prostaglandins and bicarbonate production 3- Sucralfate binds bile salts (used to treat individuals with biliary gastritis  Mucosal protective agents 1- Sucralfate Adverse Effects: Constipation Precautions: 1)should be avoided in patients with renal failure (because some aluminium is absorbed). 2)Should be taken at least 2 hours after the administration of other drugs as phenytoin and digoxin (forms a viscous layer in the stomach that may inhibit absorption of drugs)  Mucosal protective agents 2- Prostaglandin Analogs: (Misoprostol = Synthetic analog of prostaglandin E1) Prostaglandins produced by the gastric mucosa Prostaglandin Mechanism of gastric protection PGE1 1. Inhibit histamine-stimulated gastric acid secretion 2. Stimulation of mucin and bicarbonate secretion 3. Increase mucosal blood flow PGI2 (prostacyclin) Inhibit histamine-stimulated gastric acid secretion  agents 2-Misoprostol Actions: 1.Inhibit histamine-stimulated gastric acid secretion 2.Stimulation of mucin and bicarbonate secretion 3. Increase mucosal blood flow Therapeutic uses: Prevent ion of NSAID-induced mucosal injury (rarely used because it needs frequent administration – 4 times daily)  Mucosal protective agents 2-Misoprostol Adverse Effects: 1.Diarrhea, with or without abdominal pain and 2.Exacerbations of inflammatory bowel disease and should be avoided in patients with this disorder. Contraindications: 1.Inflammatory bowel disease 2.Pregnancy (may cause abortion)  Mucosal protective agents 3- Colloidal bismuth compounds (Bismuth subsalicylate) Pharmacological actions: 1- Undergoes rapid dissolution in the stomach into bismuth and salicylates. 2- Salicylates are absorbed 3- Bismuth coats ulcers and erosions protecting them from acid and pepsin and increases prostaglandin and bicarbonate production Uses: -Treatment of dyspepsia and acute diarrhoea  Specific acid dyspeptic disorders and therapeutic strategies Gastro- 1- Mild: H2 receptor antagonists (twice daily) esophageal reflux 2- Sevre: Proton pump inhibitors once daily (for disease 8 weeks) 3- Antacids are recommended only for the patient with mild, infrequent episodes of heartburn. 4- Severe with nocturnal acid breakthrough: proton pump inhibitors twice daily. If symptome persist, H2 receptor antagonist is added at night Helicobacter pylori Triple therapy for 14 days: infection (H. pylori) [Proton pump inhibitor + clarithromycin 500 mg + (metronidazole 500 mg or amoxicillin 1 g)] twice a day. NSAID-related 1- Proton pump inhibitors (best) Ulcers 2- H2 receptor antagonist 3- Misoprostil Peptic ulcer Proton pump inhibitors Thank you for your Attention Antiemetics  Emesis The act of vomiting is a forceful evacuation of gastric contents through the mouth. It is often preceded by nausea and may be retching Vomiting can be a valuable but it is also an unwanted side effect of cancer chemotherapy as well as opioids, general anaesthetics e.t.c. Common etiologies of nausea and vomiting GI tract disorders Other CNS disorders  toxins, infections,  migraine, neoplasm, obstruction, bleed inflammation, motility Vestibular disorders disorders Non-GI infections Metabolic/endocrine  liver, CNS, renal,  DKA, uremia, adrenal pneumonia, others insufficiency, hyper- or Pregnancy hypothyroidism, hyper- or hypoparathyroidism Visceral inflammation Alcohol intoxication  pancreas, GB, peritoneum Psychogenic Myocardial ischemia Radiation exposure or infarction Medications Medications that often cause nausea and vomiting Cancer Metformin chemotherapy Anti-parkinsonians  e.g. cisplatin  e.g., bromcryptine, L-DOPA Analgesics Anti-convulsants  e.g. opiates, NSAIDs  e.g., phenytoin, Anti-arrythmics carbamazepine  e.g., digoxin, quinidine Anti-hypertensives Antibiotics Theophylline  e.g., erythromycin Anesthetic agents Oral contraceptives Neurotransmitter in Emesis The neurotransmitters that have been implicated in vomiting include: Acetylcholine, Histamine, 5-HT, and Dopamine H1R, AchMR found on the vestibular nuclei and D2 R and 5-HT R are on the CTZ (floor of the 4th ventricle) AchMR also on vomiting centre (brain stem)  Pathophysiology of Emesis Cancer chemotherapy Cerebral cortex Opioids Smell Sight Anticipatory emesis Thought Chemoreceptor Vomiting Centre Vestibular Trigger Zone (medulla) Motion nuclei (CTZ) sickness Muscarinic, 5 HT3 & Muscarinic (Outside BBB) Histaminic H1 Histaminic H1 Dopamine D2 5 HT3,,Opioid Chemo & radio therapy Receptors Gastroenteritis Pharynx & GIT 5 HT3 receptors Emetic drugs In the event of swallowing a toxic agent, there could be a need to stimulate emesis. Ipecacuanha (emetine and cephaeline)acts locally in the stomach Performs its irritant action via its constituents  Now answer this question Which group of drugs can be used as antiemetics ? Serotonin 5 HT3 Antagonists Dopamine D2 Antagonist Anticholinergics H1 Antihistaminics Cannabinoids Serotonin 5 HT3 Antagonist Drugs Available Ondansetron 32 mg/day Granisetron 10 g/kg/day Dolasetron 1.8 mg/kg/day Indications Chemotherapy induced nausea & vomiting – given 30 min. before chemotherapy. Postoperative & postradiation nausea & vomiting Adverse Effects Excellent safety profile Headache & constipation All three drugs cause prolongation of QT interval, but more pronounced with dolasetron.  Dopamine D2 Antagonist Antagonise D2 receptors in CTZ. Drugs available Metoclopramide 2.5 mg b.d Domperidone 10 mg b.d Both drugs are also prokinetic agents due to their 5HT4 agonist activity. Domperidone – oral ; Metoclopramide – oral & i.v Metoclopramide crosses BBB but domperidone cannot.  Now answer this question Which is a better antiemetic – Metoclopramide or Domperidone ? As CTZ is outside BBB both have antiemetic effects. But as metoclopramide crosses BBB it has adverse effects like extrapyramidal side effects.. Domperidone is well tolerated.  Phenothiazines & Butyrophenones Phenothiazines Prochlorperazine Promethazine (H1 antagonist) Chlorpromazine Phenothiazines are antipsychotics with potent antiemetic property due to D2 antagonism. Butyrophenone Droperidol Droperidol used for postop. nausea & vomiting, but  H1 Antihistaminics Most effective drugs for motion sickness Drugs available Meclizine Cyclizine Dimenhydrinate Diphenydramine Promethazine – Used in pregnancy, used by NASA for space motion sickness  Anticholinergics Scopolamine (hyoscine) – used as transdermal patch for motion sickness Cannabinoids Dronabinol – used as adjuvant in chemotherapy induced vomiting. It is a psychoactive substance Nabilone  Cont’d Cannabinoids (nabilone): inhibit at CTZ Orally well absorbed with half life of 120min. Metabolites excreted in the urine and faeces Drowsiness, dizziness, dry mouth mood changes, hallucinations. Treats vomiting caused by cytotoxic anticancer drugs. Steroids (dexamethasone) used in combination with ondansetron or chlopromazine.  Now answer this question A physician prescribed Tab.Ondansetron for prophylaxis of motion sickness. Even though ondansetron is a potent antiemetic it didn’t produce any effect in this patient. Can you explain why ? Manikandan 61 Explanation : Vestibular nuclei has only muscarinic and H1 histaminic receptors. Manikandan 62 Manikandan 63