Pharmacology of GI Diseases GI Pharmacology 1. Peptic ulcer disease (PUD) 1. Peptic ulcer disease (PUD) 2. Gastroesophageal reflux dis. (GERD) 2. Gastroesophageal reflux dis. (GERD) 3. Anti-emetics 3. Anti-emetics 4. Constipation 4. Constipation 5. Diarrhea 5. Diarrhea Peptic Ulcer or Ulcer Location: Stomach, DuodenumLocation: Stomach, Duodenum Time course: Acute, Chronic (= 4)Time course: Acute, Chronic (= 4) Importance and incidence:Importance and incidence: 1 - Chronic DU (10% total population) 2 - Acute Stomach U (NSAIDs) 3 - Chronic Stomach U (Cancer) 4 - Acute DU (Rare) Gastric Ulcer Duodenal Ulcer Peptic Ulcer or Ulcer Aggressive and Defensive factors factors Aggressive factors: Acid, pepsin, bile Defensive factors: Mucus, bicarb, PGs, blood flow, regeneration blood flow, regeneration Peptic Ulcer or Ulcer Drugs that reduce intragastric acidity Drugs that promote regeneration ANTI HP DRUGS Peptic Ulcer or Ulcer Acid: Normal pH (4.5) pH after meal (1.5) Nocturnal pH (Hyperacidity) DU: Hyperacidity present; not always Others: Less Hyperacidity Peptic Ulcer or Ulcer Acid: = HCl = HCl Origin = Parietal cells Origin = Parietal cells Neighbors = Mast cells Neighbors = Mast cells Mast cells receptors: A Ch, Gastrin, Hist Mast cells receptors: A Ch, Gastrin, Hist Parietal cell receptors: Hist, A Ch, Gastrin, Ca and PGEs Parietal cell receptors: Hist, A Ch, Gastrin, Ca and PGEs Peptic Ulcer or Ulcer Acid: Acid: Origin = Parietal cells, with help Origin = Parietal cells, with help of Carbonic Anhydrase of Carbonic Anhydrase Secretion = Proton pump (H/K ATPase) Secretion = Proton pump (H/K ATPase) Peptic Ulcer or Ulcer Anti-Acid:Antacids: Anti receptors, Anti pump, Anti (Alkaline), Anti receptors, Anti pump, Anti (Alkaline), Coating agents, Vomiting ! Coating agents, Vomiting ! Helicobacter pylori Mucus dweller Mucus dweller Gram neg. rodGram neg. rod World wide distribution World wide distribution Acquired in childhoodAcquired in childhood More prevalent in FOGHARA and elderlyMore prevalent in FOGHARA and elderly Helicobacter pylori May be spread:May be spread: 1.Oral-oral 2.Oral-fecal 3.Water supply Some people have organism and no lesionSome people have organism and no lesion Helicobacter pylori Biopsy and culture, Serology,Biopsy and culture, Serology, Meretek UTB, breath testMeretek UTB, breath test Meretek UTB tests presence of organismtests presence of organism patient drinks C 13 ureapatient drinks C 13 urea organism converts urea into CO 2organism converts urea into CO 2 patient breathes into a containerpatient breathes into a container 90 to 95 percent accurate90 to 95 percent accurate Drug Therapy AntacidsAntacids Antihistamines, Anti A ChAntihistamines, Anti A Ch Proton pump inhibitors (PPI)Proton pump inhibitors (PPI) Coating agents (Sucralfate)Coating agents (Sucralfate) PGE 1 analog PGE 1 analog AntibioticsAntibiotics Antacids 1. Weak bases: S 1. Weak bases: Al(OH) 3, Mg(OH) 3 S 2. Differ widely: Acid neutralizing capacity TasteCost 3. Liquids better than tablets 4. Increase healing 5. Large daily doses given ADR 1. Sodium bicarbonate : systemic alkalosis 2. Magnesium: diarrhea 3. Aluminum: constipation 4.Binds certain drugs in the GI tract: tetracycline, ciprofloxacin, captopril 5.Give antacids 2 hours AFTER other drugs Antihistamines (H 2 Blockers) PreparationsPreparations cimetidine; ranitidine; famotidine; nizatidine cimetidine; ranitidine; famotidine; nizatidine Reduce acid secretionReduce acid secretion Heal ulcers % in 8 WHeal ulcers % in 8 W Bedtime use (total daily dose)Bedtime use (total daily dose) 24 24 PPI: Omeprazole Inhibits the parietal cell proton pump (PP) (H/K ATPase pump):Inhibits the parietal cell proton pump (PP) (H/K ATPase pump): Prolonged duration of action Very effective Used for hypersecretory states, acute or chronic DU, esophagitisUsed for hypersecretory states, acute or chronic DU, esophagitis Similar drug: LansoprazoleSimilar drug: Lansoprazole Use 2 hours before meal :Use 2 hours before meal : Sucralfate No Anti acid effectNo Anti acid effect Forms mucilage & coats ulcerForms mucilage & coats ulcer Minimally absorbedMinimally absorbed Heals ulcerHeals ulcer Only approved for DUOnly approved for DU Misoprostol An analog of PGE 1An analog of PGE 1 Inhibits gastric acid secretionInhibits gastric acid secretion Cytoprotective actionsCytoprotective actions Misoprostol: ADR Nausea,Vomiting, DiarrheaNausea,Vomiting, Diarrhea Others - mainly gynecological (cramps, hypermenorrhea, menstrual disorders)Others - mainly gynecological (cramps, hypermenorrhea, menstrual disorders) Criminal abortion Criminal abortion Contraindication: PregnancyContraindication: Pregnancy H. Pylori Eradication Standard of care Heals ulcerHeals ulcer Reduces recurrence from % to about 15%Reduces recurrence from % to about 15% Eradication rates vary:Eradication rates vary: 1.Organism sensitivity 2.Antibiotic protocol 3.Patient compliance Triple therapy for H. pylori 2 weeks Bismuth subsalicylate - 2 tabs qid Metronidazole mg qid Tetracycline mg qidBismuth subsalicylate - 2 tabs qid Metronidazole mg qid Tetracycline mg qid Followed by:Followed by: H 2 blocker - full dose for 2 to 4 weeksH 2 blocker - full dose for 2 to 4 weeks Triple therapies 2 W THE BEST Lansoprazole 30 mg BID Amoxicillin 1 gram BID Clarithromycin 500 mg BID Dual Therapies - 4 weeks Clari + Omep Clari + Omep Clarithromycin 500 mg TID X 2 W Omeprazole 40 mg/day X 2 W then, 2 more weeks of omep 20 mg/day Suggestions Mild: Antacids or any H 2 (-)Mild: Antacids or any H 2 (-) High risk patients on NSAIDs: misoprostolHigh risk patients on NSAIDs: misoprostol GU or DU:GU or DU: Antibiotics Triple therapy if compliantTriple therapy if compliant Dual therapies if not compliantDual therapies if not compliant GI Pharmacology 1. Peptic ulcer disease (PUD) 1. Peptic ulcer disease (PUD) 2. Gastroesophageal reflux dis. (GERD) 2. Gastroesophageal reflux dis. (GERD) 3. Anti-emetics 3. Anti-emetics 4. Constipation 4. Constipation 5. Diarrhea 5. Diarrhea Esophagus Gastric pressure more than esophageal pressure Diaphram Negative pressure Positive pressure Lower esophageal sphincter GERD Pathophysiology Lungs GERD Gastric pressure higher than intraesophageal pressureGastric pressure higher than intraesophageal pressure Predisposing factors: Diet, others...Predisposing factors: Diet, others... Consequences: Esophageal ulcersConsequences: Esophageal ulcers Strictures, scarring, cancerous lesions Incidence of heartburn: 50 % ?Incidence of heartburn: 50 % ? GERD: Medical Treatment Antacids - relieve symptomsAntacids - relieve symptoms Alginic acid (Gaviscon) ???Alginic acid (Gaviscon) ??? H 2 blockers:H 2 blockers: Will not relieve an acute attack 75% report relief of symptoms Maintenance: H 2 (-) + Omeprazole Maintenance: H 2 (-) + Omeprazole Omeprazole in GERD Very effective, long actingVery effective, long acting Reserve for non-responders, severe GERDReserve for non-responders, severe GERD Takes time to reduce acidTakes time to reduce acid not good for acute relief acid blockade is profound and long-lasting May become first line drug for GERDMay become first line drug for GERD Prokinetic Agents Increase gastric emptyingIncrease gastric emptying Not tolerated wellNot tolerated well Generally not used aloneGenerally not used alone Two major drugs:Two major drugs:metoclopramide domperidone domperidone GI Pharmacology 1. Peptic ulcer disease (PUD) 1. Peptic ulcer disease (PUD) 2. Gastroesophageal reflux dis. (GERD) 2. Gastroesophageal reflux dis. (GERD) 3. Anti-emetics & Anti-Obesity 3. Anti-emetics & Anti-Obesity 4. Constipation 4. Constipation 5. Diarrhea 5. Diarrhea Anti emetic drugs - - - - ( - ) - - ( ...) - Pathophysiology of nausea / vomiting CortexCortex Vestibular apparatus GI tract Chemoreceptor Trigger Zone (CTZ) Neurotransmitters l Acetylcholine l Dopamine l Histamine l Serotonin Neurotransmitters l Acetylcholine l Dopamine l Histamine l Serotonin Vomiting center : : : Nausea and vomiting Things to remember Principal sites of pathway Principal sites of pathway Cerebral cortex (Attention) Cerebral cortex (Attention) Vestibular apparatus Vestibular apparatus CTZ CTZ GI tract (Attention) GI tract (Attention) Anti emetic drugs Vomiting center Vomiting center, in the 4 th ventricle, is excited by: H 1, M 1, NK 1 & 5-HT 3 H 1, M 1, NK 1 & 5-HT 3 receptors. antagonist H 1 antagonist : Promethazine, Prochlorperazine antagonist M 1 antagonist : Meclizine, Diphenhydramine antagonist D 2 antagonist : Metoclopramide, Domperidon NK 1 antagonist : Aprepitant 5HT 3 antagonist : Ondansetron, Granisetrone CTZ Receptors: 5HT 3, NK 1 & D 2Receptors: 5HT 3, NK 1 & D 2 5HT 3 antagonists: Ondansetron, Granisetron5HT 3 antagonists: Ondansetron, Granisetron NK 1 antagonist: AprepitantNK 1 antagonist: Aprepitant D 2 antagonist: MetoclopramideD 2 antagonist: Metoclopramide In chemotherapy use combination:In chemotherapy use combination: (Granisetron + Aprepitant + Corticosteroid) (Granisetron + Aprepitant + Corticosteroid) Antiemetic drugs Second line Second line Dexamethazone: reduces peritumoral oedema, first line for raised intracranial pressure. Ondansetron: 5HT 3 - blocks gut serotonin release. Marijuana: for cancer vomitings Nausea and vomiting Things to remember * Common in cancer patients ( %) * Common in cancer patients ( %) * Symptomatic treatment is necessary * Symptomatic treatment is necessary * Remember gastric empting * Remember gastric empting * Please differentiate: * Please differentiate: OBSTRUCTIVE vs NON-OBSTRUCTIVE OBSTRUCTIVE vs NON-OBSTRUCTIVE ... ... Nausea and vomiting Yademan bashad Appropriate route of drug administration SUBCUTANEOUS SUBCUTANEOUS GI Pharmacology 1. Peptic ulcer disease (PUD) 1. Peptic ulcer disease (PUD) 2. Gastroesophageal reflux dis. (GERD) 2. Gastroesophageal reflux dis. (GERD) 3. Anti-emetics & Anti Obesity 3. Anti-emetics & Anti Obesity 4. Constipation 4. Constipation 5. Diarrhea 5. Diarrhea Powerpoint Templates : - - : - - : - - : - - ... ... ... ... Phentermine: releases norepinephrine Phentermine: releases norepinephrine increases synaptic NE increases synaptic NE L HTTP: a serotonine precursor L HTTP: a serotonine precursor increases synaptic serotonine increases synaptic serotonine Sibutramine: inhibits norepinephrine Sibutramine: inhibits norepinephrine & serotonine re - uptake and & serotonine re - uptake and increases synaptic NE and serotonine increases synaptic NE and serotonine Orlistat: inhibits gut lipid absorption Orlistat: inhibits gut lipid absorption Any other drug ? Orlistat A LIPOSTATIN derivastive: Natural inhibitor of pancreatic lipase 60 120 Any other drug ? Cholesterol absorption inhibitors Ezetimibe blocks the intestinal Ezetimibe blocks the intestinal absorption of cholesterol absorption of cholesterol? ( ) Constipation Chronic constipation is a concernChronic constipation is a concern Before laxatives, try: Before laxatives, try: diet, expand fiber, increase water exercise Laxatives BULK Osmotic Stimulants Softeners Bulk laxatives Not absorbed or digestedNot absorbed or digested Expand in water to provide bulkExpand in water to provide bulk Preparations:Preparations: BRAN BRAN Psyllium Psyllium Osmotic laxatives Preparations Magnesium salts Sodium phosphate Lactulose Stimulants Preparations Preparations C astor oil C astor oil Bisacodyl Bisacodyl Softeners 1. Soaps Mechanism: hydration Mechanism: hydration 2. Mineral oil Mechanism: lubrication Mechanism: lubrication Diarrhea: Pathophysiology Basic disturbance is reduced water and electrolyte absorption from the bowel Normal GI absorption is highly efficient Fluid Input Per Day Source Liters Diet2 Saliva1 Gastric juice2 Bile1 Pancreatic juice2 Small intestinal1 TOTAL9 liters per day Rational Therapy Treat the causeTreat the cause Chronic diarrhea is a cause for concernChronic diarrhea is a cause for concern Be especially careful with childrenBe especially careful with children Antidiarrheal therapy may be contraindicatedAntidiarrheal therapy may be contraindicated Drug Treatment W A T E R Opiates: Paregoric, Loperamide W A T E R Opiates: Paregoric, Loperamide Diphenoxylate (synthetic opioid): Diphenoxylate (synthetic opioid): ( NO ADDICTION !! ) ( NO ADDICTION !! ) Adsorbents: B ismuth subsalicylate Adsorbents: B ismuth subsalicylate Summary PayanPayan