Drugs Used in Disorders of the Gastrointestinal System by Marc Imhotep Cray, M.D.

Radiograph of abdomen with radiopaque contrast (barium enema). Widmaier, EP. Vanderâ&#x20AC;&#x2122;s human physiology 13th Ed. New York: McGraw-Hill, 2014.

Marc Imhotep Cray, M.D.

Core Concepts and Learning Objectives 1. List the 5 different groups of drugs used in peptic ulcer disease. 2. Describe the mechanism of action of omeprazole and related drugs. 3. List 7 different drugs used in the prevention of chemotherapyand (or) radiation-induced emesis and identify the receptors with which they interact. 4. Describe the mechanism of action, clinical uses, and adverse effects of metoclopramide. 5. Identify 2 drugs commonly used as antidiarrheal agents and 4 drugs with different mechanisms that are used as laxatives. 6. Identify drugs used in the management of inflammatory bowel disease and irritable bowel syndrome. Marc Imhotep Cray, M.D.

Core Concepts & Learning Objectives cont. 7. Describe the most common causes of constipation. 8. Explain the mechanisms of action, indications, and contraindications for drugs used for the relief of constipation. 9. Describe an appropriate pharmacologic plan of therapy to palliate the symptom of constipation. 10. Explain the pathophysiology of nausea and vomiting. 11. Explain the mechanisms of action, indications, and contraindications for antiemetics. 12. Describe an appropriate pharmacologic plan of therapy to palliate the symptoms of nausea and vomiting. Marc Imhotep Cray, M.D.

Topical Outline Introduction  Disorders of Gastrointestinal Tract_Classification chart  Disorders of Liver, Gallbladder, and Exocrine Pancreas_Classification chart  Drugs Used in Gastrointestinal Disorders_Classification chart  Select GI Tract-related Abbreviations  GI Tract Pharmacology High-Yield Terms

Overview of Gastrointestinal (GI) tract Pharmacology Function and Regulation of the GI System (A Rapid Review) Disorders of Colonic Motility: Diarrhea, Constipation  Functional Disorder of Large Intestine: Irritable Bowel Syndrome (IBS) Marc Imhotep Cray, M.D.

Topical Outline cont. Inflammatory bowel disease (IBD): Crohn’s disease and ulcerative colitis Protozoal GI Infection (Giardiasis) Peptic Ulcer Disease Gastroesophageal Reflux Disease Pancreatitis (acute vs chronic) Gallstones (Cholelithiasis) Liver Physiology, Pathology and Pharmacology Nausea and Vomiting (Chemotherapy and Radiation-induced Emesis [CIE&RIE])

Marc Imhotep Cray, M.D.

Introduction to GI Tract

Marc Imhotep Cray, M.D.

Introduction  Gastrointestinal tract is basically a tube that runs through center of body from mouth to anus  This tube consists of following organs: o Mouth o Pharynx o Esophagus o Stomach o Small intestine o Large intestine  Although organs are continuous w one another each has important anatomical modifications that allow it to carry out its specific functions Marc Imhotep Cray, M.D.

Introduction  Accessory digestive organs exist outside GI tract however, each of these organs empties secretions into tract that contribute to process of digestion  Accessory digestive organs include: o Salivary glands o Liver o Gallbladder o Pancreas

Marc Imhotep Cray, M.D.

Structure of GI Tract

Marc Imhotep Cray, M.D.

Fox SI. Human Physiology, 12th ed. New York, NY: McGraw-Hill, 2011.

Four major processes GI tract carries out:

Widmaier EP, Raff H, Strang KT. Vanderâ&#x20AC;&#x2122;s Human Physiology: The Mechanisms of Body Function, 14th Ed. New York, NY: McGraw-Hill Education, 2016.

Marc Imhotep Cray, M.D.

Introduction cont.  In addition to its main function of digestion and absorption of food, GI tract is one of major endocrine systems (largest)  Also, GI tract has its own integrative neuronal network, enteric nervous system (ENS)  contains almost same number of neurons as spinal cord  ENS is site of many common pathologies from simple dyspepsia to complex autoimmune conditions such as Crohn’s disease o medicines for treating GI disorders comprise 8% of all prescriptions

blood vessels and glands (exocrine, endocrine and paracrine) of GI tract are under both neuronal and hormonal control Marc Imhotep Cray, M.D.

Introduction  This series of presentation will focus on medications used to treat common medical conditions involving GI tract, including 1) 2) 3) 4) 5) 6) 7) 8)

Peptic ulcers (PUD) Gastroesophageal reflux disease (GERD) Chemotherapy-induced emesis (CIE or CINV), Diarrhea Constipation Irritable Bowel Syndrome (IBS) Inflammatory Bowel Disease (IBD) and Accessory digestive organ (liver, pancreas and gallbladder) disorders  (See GI section of ICM_ Systems-based Pathophysiologic High Yield Cases)

 In each case mechanisms of action & therapeutic effects of drugs discussed will be considered against their potential adverse effects (AEs), drug-drug & patient-drug interactions  (See companion eNotes: Gastrointestinal Tract Pharmacology and Autocoids, Antiinflammatory and Immunosuppressive Agents) Marc Imhotep Cray, M.D.

Introduction  Several drugs described in other modules also find application in treatment of GI disorders  For example, the meperidine (opiate) derivative diphenoxylate decreases peristaltic activity of gut is useful in treatment of severe diarrhea  Dexamethasone & methylprednisolone (corticosteroids) are effective against mildly to moderately emetogenic chemotherapy

 Other drugs discussed are used almost exclusively to treat GI tract disorders



For example, H2- receptor antagonists (eg., cimetidine) & proton pump inhibitors [PPIs] (eg., omeprazole) are used to heal peptic ulcers and in management of GERD

Marc Imhotep Cray, M.D.

Baron Lee CI. Lange Pathology Flash Cards, 2nd Ed. New York: McGraw-Hill, 2009. Marc SJ, Imhotep Cray, M.D.

Marc Imhotep Cray, M.D.

Baron SJ, Lee CI. Lange Pathology Flash Cards, 2nd Ed. New York: McGraw-Hill, 2009. 15

Pharmacologically treatable GI disorders  Include:        

Peptic ulcer disease (PUD) Gastroesophageal reflux disease (GERD) Gastroparesis (delayed gastric emptying) Nausea and Vomiting Constipation Diarrhea Irritable bowel syndrome (IBS) Inflammatory bowel disease (IBD):Crohn’s disease and ulcerative colitis Also: Viral hepatitis B & C and complications of  Pancreatitis liver disease and portal HTN (e.g., ALD)  Cholelithiasis

encephalopathy, ascites, varices & coagulopathy.

Marc Imhotep Cray, M.D.

Trevor AJ, Katzung BG, Kruidering-Hall M . Katzung & Trevorâ&#x20AC;&#x2122;s Pharmacology Examination & Board Review, 11th Ed. New York: McGraw-Hill Education, 2015.

Marc Imhotep Cray, M.D.

Select GI tract-related Abbreviations 5-ASA 5-Aminosalicylic acid 5-HT 5-Hydroxytryptamine (serotonin) ACh Acetylcholine AChE Acetylcholine Esterase CB Cannabinoid CNS Central nervous system COX Cyclooxygenase CTZ Chemoreceptor trigger zone CYP Cytochrome P450 DA Dopamine GERD Gastroesophageal reflux disease ENS Enteric Nervous System Marc Imhotep Cray, M.D.

GI Gastrointestinal H. pylori Helicobacter pylori IBD Inflammatory bowel disease M Muscarinic IBS Irritable bowel syndrome NK Neurokinin (substance P) NSAID Nonsteroidal antiinflammatory drug PPIs Proton pump inhibitors PUD Peptic ulcer disease TNF Tumor necrosis factor

GI Tract Pharmacology High-Yield Terms  Acid-peptic disease A group of disorders involving erosion or ulceration of mucosal lining of GIT; includes GERD, gastric and duodenal ulcers, nonulcer dyspepsia, and stress-related gastritis  Antiemetic A drug that reduces nausea and vomiting  Gastroesophageal reflux disease (GERD) Esophageal irritation or inflammation due to reflux of stomach acid; also known as heartburn  Gastroparesis Paralysis of muscles of stomach and possibly other parts of GIT due to damage to gastrointestinal nerves or muscle; common in advanced diabetes and advanced Parkinson’s disease Marc Imhotep Cray, M.D.

High-Yield Terms cont. Inflammatory bowel disease (IBD) Inflammatory disorder involving irritation and ulceration of colon and rectum (ulcerative colitis) or colon plus more proximal parts of the GI tract (Crohn’s disease), alone with systemic manifestations Irritable bowel syndrome (IBS) Disease of unknown origin characterized by episodes of abdominal discomfort and abnormal bowel function (diarrhea, constipation, or both) Prokinetic A drug that promotes gastrointestinal motility Proton pump The parietal cell H+/K+ ATPase that uses energy of ATP to secrete protons into the stomach; final common target of drugs that suppress acid secretion Marc Imhotep Cray, M.D.

Overview of Gastrointestinal (GI) tract Pharmacology

Marc Imhotep Cray, M.D.

Overview of GI tract Pharmacology  Gastrointestinal (GI) tract [GUT] is an epithelium-lined muscular tube that runs from mouth to anus  Major functions of GI system are food digestion, nutrient absorption, and delivery of nutrients to blood for distribution  Other functions are excretion of waste and secretion of hormones into blood for delivery to distal targets & same system  GI system has an important role in fluid & electrolyte balance 

normal route for water & salt intake and a potential source of fluid and electrolyte loss fluid, electrolyte & acid-base disturbances

Marc Imhotep Cray, M.D.

Overview of GI Tract Pharm (2) During digestion, a large volume of digestive secretions are added to ingested, chewed, and swallowed food 

Nearly all of this combined mixture must be reabsorbed to avoid major disturbances in fluid-electrolyte and acid-base balance

 Small intestine provides a large surface area for absorption of nutrients and drugs

 Substances are moved through GI tract by peristalsis 

Abnormally fast or slow peristalsis can disrupt absorption of nutrients, drugs, and water origin of most GI dysfunctions including: constipation, diarrhea, peptic ulcer disease, gastroesophageal reflux disease (GERD), and emesis

Marc Imhotep Cray, M.D.

Overview of GI Tract Pharm (3) Constipation Laxatives can be used for Tx constipation cause emptying of colon and defecation by stimulating peristalsis or by adding more bulk or water to feces

Diarrhea Opioids (diphenoxylate and loperamide) are most effective drugs for controlling severe diarrhea  Diarrhea can also treated with antiinflammatory drugs such as NSAIDs (indomethacin) and aspirin  Bismuth compounds (OTC) are used for simple diarrhea Marc Imhotep Cray, M.D.

Overview of GI Tract Pharm (4)  Peptic ulcer disease (an acid-peptic disease) is caused by an erosion of mucosal layer of stomach or proximal small intestine (duodenum)  Helicobacter pylori infection is most common cause  GERD is a similar disorder (acid-peptic disease) that occurs in esophagus and is treated with similar antisecretory medications  PUD is best treated by a combination of lifestyle changes and medication combinations

Marc Imhotep Cray, M.D.

Overview of GI Tract Pharm (5) Histamine H2-receptor antagonists are firstline drugs for peptic ulcers  Clin. Effect reduce stomach acidity without (for most part) producing significant adverse effects (AEs) cimetidine is an exception, as it can cause problematic effects and interactions

Proton pump inhibitors (PPIs) are effective at reducing gastric acid secretion by irreversibly inhibiting H+/K+ ATPase, which blocks final step in acid secretion an enzyme expressed by stomach parietal cells  PPIs are therapeutically effective but not uncommonly must be discontinued if long-term b/c of an AE profile (increased incidence of respiratory & enteric infections) o reduction in acid production may permit bacterial overgrowth Marc Imhotep Cray, M.D.

Overview of GI Tract Pharm (6)  Antacids directly neutralize stomach acid most immediate relief of acid pain, however, duration of action is limited by stomach-emptying time  Neutralize stomach acid and blunt reflux disease symptoms  firstline drugs for GERD  Useful in pts who can’t tolerate H2 blockers or PPIs in PUD NB. “Although this class of agents are referred to as antacids, the term antacid has much wider use and applies to each of many classes of drugs that reduce acid secretion. The more appropriate term for agents in class is buffer, as describes their chemical mechanism and distinguishes them from other classes.” Bardal SK, Waechter JE, Martin DS. Applied Pharmacology. St. Louis, Missouri: Saunders, 2011. Marc Imhotep Cray, M.D.

Overview of GI Tract Pharm (7) Buffers (antacids) cont.  Systemic antacid Sodium bicarbonate (rarely used due to AEs) o It is readily absorbed into body, thus o AEs common, including metabolic alkalosis, hypernatremia, fluid retention, & acid rebound, due to high gastric pH  Nonsystemic antacids are poorly absorbed into body o Magnesium hydroxide induces AE of diarrhea, whereas o aluminum hydroxide induces constipation thus, magnesium hydroxide and aluminum hydroxide are frequently combined to create an antacid preparation w little effect on GI motility o Calcium carbonate (Tums) has more AEs, including hypercalcemia (e.g., milk alkali syndrome), acid rebound, and constipation Marc Imhotep Cray, M.D.

Overview of GI Tract Pharm (8) ď ą Several drugs are available to treat nausea, vomiting (N/V), and motion sickness ď&#x201A;§ These agents include o o o o o o o

Histamine-H1 (1st generation) antagonists Corticosteroids Phenothiazines(D2 receptor antagonist), Benzodiazepines Serotonin(5-HT3) receptor antagonists Substituted benzamides (metoclopramide) Substance P/Neurokinin-1 receptor blocker

Marc Imhotep Cray, M.D.

Function and Regulation of the Gastrointestinal System

Marc Imhotep Cray, M.D.

Functions of Organs of Digestive System

Marc Imhotep Cray, M.D.

Widmaier EP, Raff H, Strang KT. Vanderâ&#x20AC;&#x2122;s Human Physiology: The Mechanisms of Body Function, 14th Ed. New York, NY: McGraw-Hill Education, 2016.

Regulation of gastrointestinal function  GI (or digestive) tract contains 3 types of sensory receptors sensitive to chemical or mechanical changes, include: 1. Chemoreceptors respond to chemical components within GI lumen  For example, in duodenum, chemoreceptors are stimulated by excessive amounts of hydrogen ion secreted by stomach results in a motor response that contracts pyloric sphincter (Why?)

2. Osmoreceptors breakdown of nutrients during digestion increases number of molecules and therefore osmolarity of material being processed excessive osmolarity may suggest absorption is not keeping pace with digestion can result in osmotic diarrhea 3. Mechanoreceptors respond to stretch or distension of GI tract wall Marc Imhotep Cray, M.D.

Regulation of GI function cont.  Receptor stimulation may lead to activation of any or all of following regulatory mechanisms (3) within GI tract:  Autonomic Nervous System  Intrinsic nerve plexuses (Enteric Nervous System) o independent of CNS intratract reflexes provide a mechanism for self-regulation of tract and help to coordinate activity of organs within it

 Extrinsic autonomic nerves (PANS & SANS) o effects of ANS divisions oppose each other: parasympathetic stimulates most digestive activities, while sympathetic system inhibits them

 Gastrointestinal hormones o travel in circulatory system to other regions of tract, and influence of effector cells in that region Marc Imhotep Cray, activity M.D.

Enteric Nervous System (ENS)  Nervous system (CNS & ANS) exerts a profound influence on all digestive processes, including   motility,  ion transport assoc. with secretion and absorption, and  blood flow  Some of this control emanates from connections betw. digestive system and CNS--but just as important--digestive system is endowed with its own, local nervous system, referred to as enteric or intrinsic nervous system Marc Imhotep Cray, M.D.

Enteric Nervous System (2)  Principal components of ENS  2 networks or plexuses of neurons both are embedded in wall of digestive tract and extend from esophagus to anus  Myenteric (Auerbach’s) plexus is located betw. longitudinal and circular layers of muscle in tunica muscularis controls and coordinates motility Submucosal (Meissner’s) plexus located in submucosa (hence the name), betw. muscularis mucosa and circular muscle layer controls secretion and absorption, as well as, local blood flow Marc Imhotep Cray, M.D.

Functions of intrinsic system (3)  Acts as mediator of information betw. extrinsic nervous system & alimentary tract  Commands most functions of GI tube especially motility and secretion  Can execute neural function of gut without extrinsic innervations

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. 36 Philadelphia, PA: Elsevier, 2014.

Enteric Nervous System (4) Plexuses are interconnected & their ganglion cells receive preganglionic parasympathetic fibers from vagus nerve (cholinergic & excitatory) Incoming sympathetic fibers are postganglionic  In addition to innervating bld vessels, sm. mm and some glandular cells directly some sympathetics terminate in these plexuses  inhibit acetylcholine secretion

Marc Imhotep Cray, M.D.

Structure of gut in longitudinal section Not shown are smaller blood vessels and lymphatics and neural terminations on muscles.

Marc Imhotep Cray, M.D.

Widmaier EP, Raff H, Strang KT. Vanderâ&#x20AC;&#x2122;s Human Physiology: The Mechanisms of Body Function, 14th Ed. New York, NY: McGraw-Hill Education, 2016.

Integration of ANS and ENS Enteric plexuses contain 3 types of neurons most multipolar 1. Motor neurons control GI motility, secretion, and absorption  They act directly on smooth muscle, secretory cells (parietal, chief, mucous, pancreatic exocrine cells), and GI endocrine cells

2. Sensory neurons receive information from sensory receptors in mucosa and muscle  respond to mechanical, thermal, osmotic, and chemical stimuli  Chemoreceptors are sensitive to pH, glucose, & amino acids  Sensory receptors in muscle respond to stretch and tension

3. Interneurons integrate information from sensory neurons and transmit it to enteric motor neurons Marc Imhotep Cray, M.D.

Integration of ANS and ENS cont. Enteric neurons secrete ACh and Norepinephrine (NE)  Neurons that secrete ACh are o excitatory and stimulate smooth muscle contraction, o increase intestinal secretions, o release enteric hormones, and o relax (dilate) blood vessels  NE, released from extrinsic sympathetic neurons, is inhibitory and opposes biologic actions of Ach  ENS also secretes 5-hydroxytryptamine (5-HT), purines, nitric oxide and other pharmacologically active peptides Marc Imhotep Cray, M.D.

Integration of ANS & ENS Illustrated

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 41

Gastrointestinal Motility  GIT (digestive system) shows 2 basic forms of motility are:  Segmentation contractions move back and forth so that a previously constricted region relaxes and a previously relaxed region contracts o results in thorough mixing of contents w digestive enzymes and other secretions (more important in sm. intestine)

 Peristalsis contractions muscular contraction (ring of contractions) moves along length of tract o causes propulsion and forces contents forward (more important in esophagus and stomach)

Marc Imhotep Cray, M.D.

Gastrointestinal Motility cont.  Mixing ensures ingested materials are exposed to digestive enzymes and properly absorbed  In absence of mixing food is not in contact w epithelial cells that absorb nutrients  Segmentation contractions are a common type of mixing motility seen especially in small intestine segmental rings of contraction break down and mix food  Alternating contraction and relaxation of longitudinal muscle in gut wall also provides effective mixing of its contents and moves contents down the GIT Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. Marc Imhotep Cray, M.D.

Factors Affecting Gastric Emptying

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

ď ąChemoreceptors respond to various chemical components within GI lumen ď&#x201A;§ For example, in duodenum of small intestine, chemoreceptors are stimulated by excessive amounts of hydrogen ion secreted by stomach Marc Imhotep Cray, M.D.

Control of Peristalsis  Food in intestinal lumen causes smooth muscle contraction above bolus and relaxation below so that a peristaltic wave moves food down intestine from mouth to anus  ENS controls peristalsis and can work separately from CNS--but proper digestion needs– ENS and CNS coordination  ANS parasympathetic and sympathetic neurons connect CNS and digestive tract allows  sensory information to be sent to CNS,  CNS regulation of GI function and  relay of non-GI system signals Marc Imhotep Cray, M.D.

Control of Peristalsis cont.  Sympathetic stimulation inhibits GI secretion and motor activity and causes GI sphincter and blood vessel contraction  Parasympathetic stimulation increases GI secretion and motor activity and causes GI sphincter and blood vessel relax and dilation (respectively)  Important peristaltic reflexes are  gastrocolic, in which stomach distension causes colonic exodus, and  enterogastric, in which small intestine distension or irritation reduces stomach secretion and motor activity Marc Imhotep Cray, M.D.

Gastrointestinal regulatory substances (Peptides)  GI peptides-- including hormones, neurocrines, & paracrines-regulate functions of GI tract  Functions include o Contraction & relaxation of sm. mus. wall & sphincters o Secretion of enzymes for digestion o Secretion of fluid and electrolytes, and o Trophic (growth)effects on tissues of GI tract o In addition, some GI peptides regulate secretion of other gastrointestinal peptides  For example, somatostatin inhibits secretion of all GI hormones Marc Imhotep Cray, M.D.

 GI peptides are classified as:  Hormones  Paracrines or  Neurocrines  Designation is based on whether peptide is released from an endocrine cell or from a neuron of GIT or locally & route peptide takes to reach its target cell

Marc Imhotep Cray, M.D.

Costanzo LS. Physiology, 5th Ed. Philadelphia, PA: Saunders-Elsevier, 2014.

Hormones of Gastrointestinal Tract  Endocrine system regulates GI function by secreting hormones  Hormones are chemical messengers secreted into blood that modify physiology of target cells  Digestive function is affected by hormones produced in many endocrine glands but greatest control is exerted by hormones produced within GI tract  GI tract is largest endocrine organ in body endocrine cells within it referred to collectively as enteric endocrine system Marc Imhotep Cray, M.D.

Hormones of Gastrointestinal Tract cont. ď ą Three of best-studied enteric hormones are 1. Gastrin: secreted from stomach and plays an important role in control of gastric acid secretion 2. Cholecystokinin (CCK): a small intestinal hormone that stimulates secretion of pancreatic enzymes and bile 3. Secretin: a hormone secreted from small intestinal epithelial cells that stimulates secretion of bicarbonate-rich fluids from pancreas and liver Most important 3 stimuli for pancreatic secretion Marc Imhotep Cray, M.D.

Gastrointestinal Tract Hormones Table

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Note: Even during fasting, contractions (MMC= â&#x20AC;&#x153;migrating myoelectric complexâ&#x20AC;?) occur at 90-minute intervals and clear stomach of residual food. Motilin is mediator of these contractions. Marc Imhotep Cray, M.D.

Hormones of GI Tract cont.

Marc Imhotep Cray, M.D.

McInnis M, Mehta S. Step-Up to USMLE Step 1, 2015 Ed. Philadelphia, PA: Wolters Kluwer-LWW, 2015.

Gastrointestinal secretory products

Marc Imhotep Cray, M.D.

Le T, Bhushan V. First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Education, 2017.

Parietal Cell Function Regulation  Stomach’s parietal cells secrete approximately 2 L of acid a day as hydrochloric acid (HCl)  acid eradicates bacteria, aids in digestion by solubilizing food, and maintains optimal pH (1.8- 3.2) for function of pepsin, a digestive enzyme breaks down protein peptides amino acids

 H+,K+-ATPase (proton pump) is expressed on parietal cell apical (=luminal) membranes and uses energy from ATP hydrolysis to pump hydrogen ions into lumen in exchange for potassium ions into the cell Marc Imhotep Cray, M.D.

Parietal Cell Function Regulation cont.  Three regulatory molecules stimulate acid secretion-ACh, histamine, gastrin  One regulatory molecules inhibits acid secretion-somatostatin ----- Ach increases acid secretion by stimulating muscarinic (M3) receptors  Histamine, a paracrine hormone released from enterochromaffin like (ECL) cells stimulates acid secretion by activating H2 receptors  Gastrin, a hormone released by G cells (endocrine cells in gastric epithelium) increases acid release by activating gastric receptors  Somatostatin-also secreted by gastric endocrine cells (D cells)– along w prostaglandins (PGE1,PGE2) opposes stimulatory actions of gastrin Marc Imhotep Cray, M.D.

Molecular control of parietal cell acid (HCl) secretion (illustrated on next slide)  Stimulation of parietal cell acid secretion is modulated by paracrine (histamine), neurocrine (acetylcholine [ACh]), and endocrine (gastrin) pathways activate their respective receptors (H2 , M3 , and CCKB )  H2 receptor activation increases cAMP activates protein kinase A  M3 and CCKB receptor activation stimulates release of Ca+2 by Gq mediated IP3 /DAG pathway  stimulate protein kinase C activity o Protein kinase activation results in translocation of cytoplasmic tubulovesicles containing inactive H+ /K+ ATPase to apical membrane fusion of tubulovesicles with apical membrane activates H+/K+ ATPase (proton pump), which pumps H+ ions into stomach lumen o An apical membrane Cl- channel couples Cl- efflux to H+ efflux, and o An apical membrane K+ channel recycles K+ out of cell

 Net result is rapid extrusion of HCl into stomach lumen  In addition to its direct effect on CCKB receptors on parietal cells, gastrin also CCKB receptors on ECL cells to promote histamine release Marc Imhotep Cray, stimulates M.D.

Control of parietal cell acid secretion

Marc Imhotep Cray, M.D.

Golan DE, Tashjian AH (Eds.) Principles of Pharmacology : The Pathophysiologic Basis of Drug Therapy, 3rd Ed. Philadelphia, PA: Wolters Kluwer-LWW, 2012.

Control of parietal cell acid secretion (2)  Of three physiological secretagogues, histamine, acting through H2 receptors, plays dominant role b/c other two--gastrin and Ach- act partly directly and to a greater extent indirectly by releasing histamine from paracrine ECL cells (“histaminocytes”) located in oxyntic glands  H2 receptors activate H+K+ATPase by generating cAMP  Muscarinic and gastrin/CCK2 receptors function through phospholipase C → IP3– DAG pathway that mobilizes intracellular Ca2+  cAMP mediated proton pump activation also involves Ca2+ Marc Imhotep Cray, M.D.

Tripathi KD. Essentials of Medical Pharmacology, 7th Ed. New Delhi: Jaypee Brothers Medical Publishers, 2013. 59

Somatostatin and Prostaglandins  While histamine, gastrin, and ACh increase acid secretion by parietal cells somatostatin-secreting D cells and prostaglandins decrease gastric acid secretion  Somatostatin decreases acid secretion via three mechanisms:  inhibition of gastrin release from G cells by a paracrine mechanism  inhibition of histamine release from ECL cells and mast cells  direct inhibition of parietal cell acid secretion

 Prostaglandin E2 (PGE2) enhances mucosal resistance to tissue injury by:  

reducing basal and stimulated gastric acid secretion enhancing epithelial cell bicarbonate secretion, mucus production, cell turnover, and local blood flow

Marc Imhotep Cray, M.D.

Agents that stimulate and inhibit H+ secretion by gastric parietal cells.

Marc Imhotep Cray, M.D.

Costanzo LS. Physiology, 5th Ed. Philadelphia, PA: Saunders-Elsevier, 2014.

Agents that stimulate & inhibit H+ secretion (2)

Marc Imhotep Cray, M.D.

Brenner GM, Stevens CW. Pharmacology, 4th ed. Philadelphia, PA: Saunders-Elsevier, 2013.

Pancreatic Secretion ď ą Exocrine pancreas secretion is under neural and endocrine control ď ą Pancreatic secretions--major mechanism for neutralizing gastric acid in small intestine-- are stimulated by food entering stomach and chyme entering small intestine ď ą Vagus nerve innervates pancreas (and stomach) and applies a low-level stimulus for secretion in anticipation of a meal Marc Imhotep Cray, M.D.

Pancreatic Secretion cont. ď ą Most important stimuli for pancreatic secretion come from 3 enteric nervous system hormones 1. CCK is synthesized and secreted by duodenal endocrine cells in response to partly digested proteins and fats in small intestine ď&#x201A;§

CCK is released into blood and binds to receptors on pancreatic acinar cellsď&#x192; which induces digestive enzyme secretion

2. Secretin is secreted in response to acid in duodenum, stimulates pancreatic secretion of water and bicarbonate 3. Gastrin is secreted by stomach and stimulates acid secretion by parietal cells and , like CCK, digestive enzyme secretion by pancreatic acinar cells Marc Imhotep Cray, M.D.

Pancreatic Secretion Illustrated

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Defecation  Defecation (passing of feces through rectum and anus) occurs via relaxation of involuntary and voluntary internal anal sphincter and heeding rectosphincteric reflex  Defecation is prevented by external anal sphincter contraction  Rectum filling with fecal material causes urge to defecate 

When external anal sphincter relaxes, rectal smooth muscle contracts to force feces out

 Presence of food in stomach increases colon motility Marc Imhotep Cray, M.D.

Defecation cont.  A rapid parasympathetic response (stimulated GI motility by depolarizing smooth muscle cells) is initiated  CCK and gastrin mediate a slower hormonal response  Disorders of large intestine motility may be caused by emotional factors via extrinsic ANS e.g.  IBS, a disorder worsened by stress--causes constipation or diarrhea  Megacolon (Hirschsprung disease), absence of colon enteric nervous system causes intestinal contents near constriction to accumulate and severe constipation Marc Imhotep Cray, M.D.

Raffa Imhotep RB. Netter's Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. Marc Cray,Illustrated M.D.

Marc Raffa Imhotep RB. Netter's Cray,Illustrated M.D. Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Protein Digestion  Proteolytic enzymes are packaged in vesicles in an inactive form and  thus protected against harsh pH conditions of GI tract  Pepsin is a stomach enzyme derived from pepsinogen that is active at low pH o Pepsin cleaves peptide bond betw. acidic (aspartic or glutamic acid) and aromatic (phenylalanine, tyrosine) amino acids This endonuclease catabolizes proteins into smaller peptides



Trypsin is a pancreatic enzyme derived from trypsinogen that is active at slightly basic pH o Trypsin hydrolyzes peptide bonds adjacent to basic amino acids lysine and arginine thus hydrolyzing proteins into peptides

Marc Imhotep Cray, M.D.

Protein Digestion cont.  Other endopeptidases, such as chymotrypsin and enterokinase, digest proteins into multiple amino acid fragments  Pancreatic carboxypeptidase is an exopeptidase that hydrolyzes dipeptides at carboxyl end  Small intestine aminopeptidase is an exopeptidase that hydrolyzes dipeptides from amino end  Finally, dipeptidase liberates free amino acids Marc Imhotep Cray, M.D.

Protein Digestion Illustrated

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Fat Digestion  Fat digestion and absorption depend on bile  Bile is secreted by liver and released into gut by action of CCK on gallbladder  Bile acts as an emulsifier to break up fat globules to aid digestion  Pancreatic lipase is a water-soluble enzyme, thus acts only on fat globule surfaces  hydrolyzes neutral fats to give free fatty acids and 2monoglycerides  Detergent action of bile salts, esp. lecithin, is needed to disperse fat into small globules for efficient lipase action Marc Imhotep Cray, M.D.

Fat Digestion cont.  Bile also forms micelles—aggregates of free fatty acids, monoglycerides, and bile—which help transport waterinsoluble fatty acids  Micelles take fat digestion products away from digestion site to be absorbed by enterocytes these products thus, do not inhibit lipases (negative feedback)  Poor fat absorption causes excess fat in stools, or steatorrhea  Stools are bulky, pale, and odiferous

Marc Imhotep Cray, M.D.

Fat Digestion Illustrated

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Disorders of Colonic Motility: Diarrhea and Constipation

Marc Imhotep Cray, M.D.

Summary of drugs used to treat diarrhea ANTIMOTILITY AGENTS Diphenoxylate + atropine LOMOTIL Loperamide IMODIUM A-D ADSORBENTS Aluminum hydroxide ALTERNAGEL Methylcellulose CITRUCEL AGENTS THAT MODIFY FLUID AND ELECTROLYTE TRANSPORT Bismuth subsalicylate PEPTO-BISMOL

Marc Imhotep Cray, M.D.

Colonic Motility Disorder and Diarrhea  Motility patterns in colonic lumen include  peristalsis propels luminal contents toward rectum, and  those that extend contact of luminal contents w absorptive epithelial cells o Prolonging contact facilitates absorption of fluid from feces o Processes that promote propulsive patterns produce diarrhea  Diarrhea is defined as loose, watery stools that occur at least 3 times per day

Marc Imhotep Cray, M.D.

Pathophysiology of Diarrhea Diarrhea can be acute (<2 weeks duration) or chronic (>4 weeks)  Acute diarrhea is usually due to an infectious cause  Most common noninfectious causes adverse effects of medications

In simplest terms, diarrhea is due to not enough absorption (osmotic) or too much secretion (secretory)  Osmotic ( malabsorptive) diarrhea is due to malabsorbed nutrients or poorly absorbed electrolytes that retain water in GI lumen o occurs when ability to digest or absorb a particular nutrient is defective  can be due to disordered mixing (altered motility), pancreatic insufficiency (altered digestion), or damage to enterocytes or their surface transporters (altered absorption) o this type of diarrhea stops when patient fasts Marc Imhotep Cray, M.D.

Pathophysiology of Diarrhea cont.  Secretory diarrhea results when secretagogues maintain elevated rates of fluid transport out of epithelial cells into GI tract lumen o this type of diarrhea does not stop when patient fasts

Physiologic distinctions--osmotic vs secretory--are useful in both diagnosis and therapy of diarrheal disorders In transport capacity small intestine far exceeds colon (due to enormous surface area of brush border) thus, infectious, toxic, or other causes of heightened secretion in small intestine can overwhelm absorptive mechanisms in colon resulting in diarrhea Marc Imhotep Cray, M.D.

Causes and Treatment of Diarrhea  Causes Bacterial and viral infections, adverse food reactions, parasites, functional bowel disorders, IBD and medications can lead to diarrhea  b/c dehydration is caused by diarrhea, primary treatments include rehydration w electrolytes (eg, broths, soup, potassium supplements) or  slowing motility eg., w loperamide, bismuth subsalicylate, kaolin or pectin suspension  Most types of diarrhea are caused by viruses, so antibiotics are usually ineffective  Raspberry or blueberry leaves are sometimes taken w tea to alleviate some symptoms Marc Imhotep Cray, M.D.

Causes of Diarrhea       

Surgical Psychogenic and (or) neurologic Inflammatory Endocrine Irritative Dietary Malabsorptive

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Antidiarrheal Drugs  Antidiarrheal drugs aim to decrease fecal water content by increasing solute absorption and decreasing intestinal secretion and motility  Increased transit time (=decrease transit rate) facilitates water reabsorption  Tx w these medicines are reserved for pts w significant & persistent symptoms of diarrhea Main 3 agents used include 1. Opioid derivatives (diphenoxylate and loperamide) 2. Bismuth subsalicylate (Pepto Bismol) 3. Octreotide (Sandostatin) Marc Imhotep Cray, M.D.

Antidiarrheal Drugs: Opioids Opioids act directly on opioid μ-receptors to decrease transit rate, stimulate segmental (nonpropulsive) contraction, and inhibit longitudinal contraction  MOA reduce peristalsis by activating presynaptic opioid (μ) receptors in GI tract and decreasing acetylcholine release  Diphenoxylate (Lomotil) o Diphenoxylate & its active metabolite, difenoxin (Motofen), are used for Tx of diarrhea and not analgesia o used as a combination product w atropine to reduce potential for abuse o AE At high doses, may produce CNS effects, including nausea & vomiting, sedation, & constipation Marc Imhotep Cray, M.D.

Antidiarrheal Drugs: Opioids (antimotility)  Loperamide (Imodium) o opioid agonist with no CNS activity, except at very high doses, but w marked effects on intestine o It binds to opioid (μ) receptors in GI tract o PK Loperamide has a faster onset and longer duration of action than diphenoxylate o AE/Toxicity Loperamide overdose can result in severe constipation, paralytic ileus, and CNS depression o contraindicated ulcerative colitis (can induce toxic megacolon)  NB Loperamide & diphenoxylate contraindicated in children, GI obstruction, acute dysentery, UC, bacterial enterocolitis Marc Imhotep Cray, M.D.

Antidiarrheal Drugs: Bismuth subsalicylate  Bismuth subsalicylate (Pepto Bismol) 

     

Mechanism of action (antisecretory) o Selectively binds to ulcer coating protects ulcer from gastric acid o salicylate in this agent inhibits prostaglandin and chloride secretion in intestine to reduce liquid content of stools Tx diarrhea Uses: It is effective for both treatment and prophylaxis of traveler’s diarrhea and other forms of diarrhea forms a protective coating in GI tract and has direct antimicrobial activity o It is used to treat H. pylori infection (in combination therapy) also used effectively to bind toxins produced by Vibrio cholerae and Escherichia coli PK salicylate can be absorbed across intestine AE include tinnitus, nausea and vomiting It may also produce black stools and darkening of tongue (benign) Question: Why should you not give bismuth subsalicylate to children?

Marc Imhotep Cray, M.D.

Antidiarrheal Drugs: Octreotide  Octreotide (Sandostatin)  Octreotide is an analog of somatostatin  Uses o effective for Tx of diarrhea caused by short-gut syndrome and dumping syndrome o used in cases of severe diarrhea caused by excessive release of GI tract hormones including gastrin, vasoactive intestinal polypeptide (VIPomas), 5-HT (carcinoid ) o used Tx of neuroendocrine tumors of GI tract o Esophageal varices reduces portal vein blood flow o Acromegaly

 PK must be administered parenterally  AE mild GI dysfunction (abd. pain, N/V/D) and formation of gallstones due to alteration of fat absorption Marc Imhotep Cray, M.D.

Other Antidiarrheal Drugs ď ą NSAIDs such as indomethacin and aspirin thought to relieve diarrhea by blocking COX-1 and inhibiting prostaglandin synthesis ď&#x201A;§ most common AEs of aspirin are o bleeding o respiratory depression o hypersensitivity reactions o hepatitis (particularly children), and o salicylate toxicity o Contraindicated in children (except in those with Kawasaki disease) due to possibility of causing Reye syndrome= often fatal childhood hepatic encephalopathy Marc Imhotep Cray, M.D.

Treatment of Diarrhea

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Summary of drugs used to treat constipation IRRITANTS and STIMULANTS STOOL SOFTENERS Bisacodyl CORRECTOL, DULCOLAX Docusate COLACE, DOCU-SOFT Castor oil LUBRICANT LAXATIVES Senna EX-LAX, SENOKOT Glycerin suppositories BULK LAXATIVES Mineral oil Methylcellulose CITRUCEL CHLORIDE CHANNEL ACTIVATORS Psyllium METAMUCIL, FIBERALL Lubiprostone AMITIZA SALINE and OSMOTIC LAXATIVES Magnesium citrate CITROMA Magnesium hydroxide MILK OF MAGNESIA Polyethylene glycol MIRALAX Lactulose CONSTULOSE, ENULOSE Marc Imhotep Cray, M.D.

Constipation: Epidemiologic & Other Data  Population-based studies conducted in United States estimate that incidence of constipation is 12 to 19%  Female-to-male ratio of those affected is 2:1  Approximately 33% of those affected will seek medical attention for condition  Constipation is much more prevalent in developed countries than undeveloped and developing areas Marc Imhotep Cray, M.D.

Causes of Constipation  Constipation--one of most common GI problems in United States--refers to passage of small amounts of hard and dry stools  Bowel movements occur fewer than 3 times a week  Women (especially pregnant) and older adults (older than 65 years) report constipation most often  Under normal conditions, colon absorbs water as food passes through it and waste products (stool) form  Stool becomes solid b/c most of water is absorbed Marc Imhotep Cray, M.D.

Causes of Constipation cont.  Hard and dry stools occur when colon absorbs too much water or colon’s muscle contractions are slow  Common symptoms are lethargy, feeling bloated, and painful bowel movements  Causes can be metabolic & endocrine; neurogenic (involving CNS or PNS); medications; and idiopathic include     

lack of dietary fiber inadequate hydration lack of exercise IBS changes in life routines (pregnancy, travel)

Marc Imhotep Cray, M.D.

     

aging laxative abuse ignoring urges to have a BM stroke colonic disease and intestinal disease 93

Causes of Constipation

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Treatment of Constipation/ Laxatives  Constipation can be treated pharmacologically w laxatives (along with appropriate lifestyle and dietary habits)  Laxatives (stool softeners and cathartics) act primarily on large intestine to promote an  increase in fluid accumulated in bowel,  decrease net absorption of fluid from bowel, or  alter bowel motility o These actions facilitate evacuation of fecal material Caution Laxatives should not be used chronically as they may induce “laxative dependence” Contraindications Laxatives should not be used in unexplained abdominal pain or intestinal obstruction Marc Imhotep Cray, M.D.

Diagnosis & Management of Constipation

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Classes and MOA of laxatives encapsulated 1. Bulk-forming laxatives (fiber supplements) are considered safest but can interfere w absorption of some drugs 

They are taken w water & absorb water in intestine to make stool softer

2. Osmotic laxatives (saline vs non-saline) draw water into colon for easier passage of stool 3. Stimulant (irritant) laxatives cause rhythmic muscle contractions in intestines 4. Stool softeners provide moisture to stool, prevent dehydration safe in pregnancy, used after childbirth and surgery  Lubricants (mineral oil) add oil to stool allows stool to move through intestine more easily Marc Imhotep Cray, M.D.

1. Bulk-forming laxatives  Bulk-forming laxatives include psyllium (Metamucil, etc.), methylcellulose (Citrucel), and polycarbophil (Fibercon) MOA Bulk-forming laxatives are poorly absorbed from bowel lumen and retain water in bowel increased luminal mass stimulates peristalsis and produce laxation after 2-4 days  adequate hydration is required

Use agents are treatment of choice for chronic constipation AE may cause bloating and flatulence Marc Imhotep Cray, M.D.

2. Osmotic agents Uses used for both acute and chronic constipation 1. Salt-containing osmotic laxatives (saline laxatives)  Salt-containing osmotic laxatives include magnesium citrate, magnesium hydroxide, and sodium phosphates MOA poorly absorbed ions that retain water in lumen by osmosis and cause a reflex increase in peristalsis PK Salt-containing osmotic laxatives are taken orally  Sodium phosphates are also effective rectally  Onset of action typically occurs 3–6 hours after oral administration and 5–15 minutes after rectal administration o They require adequate hydration for effect AE Sodium phosphate may cause systemic adverse effects, especially in cases of renal dysfunction; include phosphatemia and hypernatremia Caution Na+ content in these agents can possibly aggravate HTN and CHF Marc Imhotep Cray, M.D.

2. Osmotic agents cont. 2. Salt-free osmotic laxatives Lack of Na+ makes these agents preferable in pts with HTN & CHF

 Salt-free osmotic laxatives include lactulose (Chronulac) MOA non-absorbable agent that retain ammonia in colon, producing osmotic effect that stimulates bowel evacuation  Polyethylene glycol– electrolyte solutions (Go-Lytely) PK may be administered rectally (PEG) or orally (lactulose) Uses  Go-Lytely is used for preoperative colon preparation  Lactulose used to prevent and treat portal systemic encephalopathy in cirrhosis and treat constipation Marc Imhotep Cray, M.D.

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3. Irritant (stimulant) laxatives  Agents include bisacodyl (Dulcolax), senna (Senokot), and cascara sagrada, castor oil MOA stimulate smooth muscle contractions resulting from their irritant action on bowel mucosa local bowel inflammation also promotes accumulation of water and electrolytes increased luminal contents stimulate reflex peristalsis, and irritant action stimulates peristalsis directly PK onset of action occurs in 6–12 hours these agents require adequate hydration AE and cautions chronic use of irritant laxatives may result in cathartic colon, a condition of colonic distention, and development of laxative dependence; Castor oil=severe cramping

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4. Stool softeners Agents include docusate sodium (Colace, etc.), glycerin, and mineral oil USE considered safe in pregnancy, after childbirth and surgery MOA  Docusate has a detergent action that facilitates mixing of water and fatty substances to increase luminal mass  Mineral oil coats fecal contents and thereby inhibits absorption of water AE  Mineral oil decreases absorption of fat-soluble vitamins  Lipoid pneumonia can develop if mineral oil is aspirated Marc Imhotep Cray, M.D.

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Functional Disorder of the Large Intestine: Irritable Bowel Syndrome (IBS)

Marc Imhotep Cray, M.D.

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Irritable Bowel Syndrome  IBS-- a functional disorder that mainly affects bowel-- causes cramping, bloating, gas, diarrhea, and constipation 

Other names for IBS are spastic colon, mucous colitis, spastic colitis, and nervous stomach

 IBS is caused by disturbed interaction of intestines, brain, and ANS that alters bowel motility (motor function) or sensory function

 Added dietary fiber may relieve constipation and diarrhea but can lead to worsened bloating, distension and flatulence

Marc Imhotep Cray, M.D.

Three classic symptoms of IBS: crampy abdominal pain, alternating constipation & diarrhea, and bloating

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IBS

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

105

Irritable Bowel Syndrome cont.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Marc Imhotep Cray, M.D.

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Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

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IBS Capsule  Recurrent abdominal pain associated with ≥ 2 of following:  Related to defecation  Change in stool frequency  Change in form (consistency) of stool  No structural abnormalities  Most common in middle-aged women

 Chronic symptoms may be diarrhea-predominant, constipationpredominant, or mixed  Pathophysiology is multifaceted Marc Imhotep Cray, M.D.

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Treatment of Irritable Bowel Syndrome  Less flatulence with polycarbophil agents than psyllium ones  Peripheral opiate antagonists (trimebutine and fedotozine), Serotonin(5HT4) antagonists (tegaserod=investigational ), and muscarinic antagonists (zamifenacin) are being studied  Trimebutine, with equal affinity for μ-, δ-, and κ-opioid receptors, stimulates small intestine transit but inhibits colonic motility  Serotonin blockers inhibit intestinal motility  Muscarinic blockers inhibit colonic motility and GI secretion  CCK and calcium channel antagonists may also be useful Marc Imhotep Cray, M.D.

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Inflammatory bowel disease (IBD): Crohnâ&#x20AC;&#x2122;s disease and ulcerative colitis

Marc Imhotep Cray, M.D.

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Crohn’s disease vs. Ulcerative Colitis* Location: (see next slide for full contrast) Crohn disease  Any portion of GI tract, usually terminal ileum and colon  Skip lesions, rectal sparing Ulcerative colitis  Colitis = colon inflammation  Continuous colonic lesions, always with rectal involvement *See: Crohn’s Disease vs Ulcerative Colitis_Capsule (Offline) Marc Imhotep Cray, M.D.

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Inflammatory bowel disease (IBD)

Le T, Bhushan V. First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Education, 2017.

Marc Imhotep Cray, M.D.

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Treatment of inflammatory bowel disease  Primary therapy for IBD (ulcerative colitis and Crohn’s disease) utilizes steroids and 5-aminosalicyclate (5-ASA), also called mesalamine, to control inflammatory process  MOA 5-ASA inhibits leukotriene production and has antiprostaglandin and antioxidant activity o Sulfasalazine, balsalazide and olsalazine (prodrugs for mesalamine) and mesalamine itself are used in mild to moderate ulcerative colitis and maintenance of remission in UC  Other immunomodulating agents are also used in IBD , including azathioprine, mercaptopurine, methotrexate, and cyclosporine Marc Imhotep Cray, M.D.

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Tx of IBD cont.  Antibodies and antibody fragments that bind to tumor necrosis factor alpha (TNF-α) block inflammatory cascade and can be used in IBD  Infliximab and adalimumab are monoclonal antibodies that bind to and inhibit TNF-α  TNF-α inhibitors are general reserved for disease refractory to more conventional therapy

 Natalizumab is another monoclonal antibody that is used in Crohn’s disease  MOA It reduces intestinal inflammation by binding α-4 integrin a molecule that mediates adhesion of leukocytes to endothelial receptors Marc Imhotep Cray, M.D.

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Protozoal GI Infection: Giardiasis

Marc Imhotep Cray, M.D.

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Protozoal GI Infection: Giardiasis  Giardiasis is most frequent cause of nonbacterial diarrhea in North America  Human giardiasis may involve diarrhea within 1 week after ingestion of cyst environmental survival form and infective stage of organism  Illness normally lasts for 1 to 2 weeks, but cases of chronic infections have lasted months to years  Chronic cases, both those with defined immune deficiencies and those without, are difficult to treat Marc Imhotep Cray, M.D.

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Giardiasis cont. Pathogenesis  Disease mechanism unknown some investigators report organism produces a toxin, but others not being able to confirm existence of toxin Treatment  Metronidazole is normally quite effective in terminating infections  Antibiotics such as albendazole, metronidazole, and furazolidone are often prescribed to treat giardiasis  paromomycin may be considered for pregnant women Marc Imhotep Cray, M.D.

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Protozoal GI Infection

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

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Protozoal GI Infection

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

119

Giardiasis Capsule Organism: Giardia Lamblia Disease: Giardiasisâ&#x20AC;&#x201D;bloating, flatulence, foul-smelling, fatty diarrheaď&#x192; often seen in campers/hikers Transmission: cysts in water Diagnosis: multinucleated trophozoites(A) or cysts (B) in stool, A B antigen detection Treatment: Metronidazole Note: Other GI parasites Entamoeba histolytica, Cryptosporidium Marc Imhotep Cray, M.D.

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Peptic Ulcer Disease Also see GI Pharm Tutorial 2, Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease

Marc Imhotep Cray, M.D.

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Summary of drugs used to treat Peptic Ulcer Disease H2 â&#x20AC;&#x201C; HISTAMINE RECEPTOR BLOCKERS Cimetidine TAGAMET Famotidine PEPCID Nizatidine AXID Ranitidine ZANTAC PROTON PUMP INHIBITORS (PPIs) Dexlansoprazole DEXILANT Esomeprazole NEXIUM Lansoprazole PREVACID Omeprazole PRILOSEC Pantoprazole PROTONIX Rabeprazole ACIPHEX

Marc Imhotep Cray, M.D.

PROSTAGLANDINS ANTIMICROBIAL AGENTS Misoprostol CYTOTEC Amoxicillin AMOXIL, TRIMOX ANTIMUSCARINIC AGENTS Bismuth compounds PEPTODicyclomine BENTYL BISMOL, KAOPECTATE ANTACIDS Clarithromycin BIAXIN Aluminum hydroxide ALTERNAGEL Metronidazole FLAGYL Calcium carbonate TUMS Tetracycline SUMYCIN Magnesium hydroxide MILK OF MAGNESIA Sodium bicarbonate NUMEROUS MUCOSAL PROTECTIVE AGENTS Bismuth subsalicylate PEPTO-BISMOL Sucralfate CARAFATE

122

Etiology of Peptic Ulcer Disease (PUD)  Etiology of peptic ulcer is not clearly known 

Probably due to an imbalance between aggressive (acid, pepsin, bile and H. pylori) and protective (gastric mucus and bicarbonate secretion, prostaglandins/PGE2, nitric oxide, high mucosal blood flow, innate resistance of mucosal cells) factors



Psychosomatic, humoral and vascular derangements have also been implicated and



Causal importance of Helicobacter pylori infection to ulcer formation and recurrence has been well documented

Marc Imhotep Cray, M.D.

Bennett PN, Brown MJ Sharma P. Clinical Pharmacology, 11th Ed. London, UK: Elsevier, 2012.

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Acid-peptic Disease Capsule  Acid-peptic diseases (GERD, PUD, esophagitis, gastritis etc.) are disorders in which gastric acid and pepsin are necessary, but usually not sufficient, pathogenic factors  acid and pepsin in stomach normally do not produce damage or symptoms b/c of intrinsic defense mechanisms o stomach is protected by a number of factors, collectively referred to as “mucosal defense,”  stimulated by local generation of prostaglandins and NO o If defenses are disrupted a gastric or duodenal ulcer may form

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Acid-peptic Disease Capsule cont.  Treatment and prevention of these acid-related disorders are accomplished by decreasing gastric acidity and enhancing mucosal defense Goals of antiulcer therapy are:  Relief of pain  Heal Ulcer  Prevent complications (bleeding, perforation, obstruction)  Prevention of relapse NB: PPIs are more efficacious and clinically favorable when compared to H2-blockers for PUD, GERD and acute stress ulcers. Marc Imhotep Cray, M.D.

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Acid-peptic Disease Capsule cont.Q  Large majority of benign gastric and duodenal ulceration is due to H. pylori infection (most of remainder due to NSAID use) 

Key role of Helicobacter pylori in pathogenesis of acid-peptic diseases has stimulated new approaches to prevention and therapy

 Colonization of stomach with H. pylori is seen in virtually all patients w a duodenal ulcer and in 70–80% of those w gastric ulcers  H. pylori stimulate increased acid secretion all pts colonized w H. pylori develop gastritis, but only about 20% have ulcers or other lesions NB: H. pylori infection is carcinogenic and is leading cause of gastric adenocarcinoma.

Marc Imhotep Cray, M.D.

126

Peptic ulcer disease: Gastric vs Duodenal Pain H pylori infection Mechanism

Other causes

Gastric ulcer

Duodenal ulcer

Can be Greater with mealsâ&#x20AC;&#x201D; weight loss ~ 70%

Decreases with mealsâ&#x20AC;&#x201D; weight gain ~ 90%

mucosal protection against gastric acid NSAIDs

mucosal protection or gastric acid secretion Zollinger-Ellison syndrome

Risk of carcinoma Other Marc Imhotep Cray, M.D.

Generally benign

Biopsy margins to rule out malignancy

Hypertrophy of Brunner glands

Meals worsen pain associated w gastric ulcer Meals relieve pain associated w duodenal ulcer

127

Peptic Ulcer complications  Hemorrhage gastric, duodenal (posterior > anterior)   

Most common complication Ruptured gastric ulcer on lesser curvature of stomach  bleeding from left gastric artery An ulcer on posterior wall of duodenum  bleeding from gastroduodenal artery

Perforated gastric ulcer

 Obstruction pyloric channel, duodenal  Perforation duodenal (anterior > posterior) 

May see free air under diaphragm with referred pain to shoulder via irritation of phrenic nerve

Marc Imhotep Cray, M.D.

Le T, Bhushan V. First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Education, 2017.

128

Peptic Ulcer Disease PharmacoTx Capsule  Triple therapy including two antibiotics and a proton pump inhibitor (e.g., amoxicillin, clarithromycin, omeprazole) will kill the Helicobacter pylori that causes most ulcers  A permanent cure can be produced in many patients  Antibiotic Tx is inappropriate for salicylate and NSAIDinduced ulcers  Metronidazole can be used in patients who are allergic to penicillins

Marc Imhotep Cray, M.D.

NB-Pts with a PUD should stop cigarette smoking , EtOH and NSAID use, reduce psychological stress, and avoid foods and beverages that trigger symptoms. 129

Helicobacter pylori Infection Overview  Helicobacter pylori, a spiral gram negative bacterium found in gastric mucous layer or adherent to epithelial lining of stomach again, causes more than 90% of duodenal ulcers and up to 80% of gastric ulcers  Approximately 66% of world’s population is infected with H pylori

H pylori in association with gastric mucosa.

Whalen K (Ed.) Lippincott Illustrated Reviews: Pharmacology 6th Ed. New York, NY: LWW, 2015.

 It causes chronic persistent and atrophic gastritis in both adults and children Marc Imhotep Cray, M.D.

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H pylori Infection Overview (2)  Before H pylori was discovered in 1982, spicy food, acid, stress, and lifestyle were considered major causes of ulcers 

Most pts had long-term pharmacotherapy w histamine antagonists (H2 blockers) and PPIs o These drugs relieve ulcer-related symptoms and gastric mucosal inflammation but do not eradicate infection o When acid suppression is removed, majority of H pylori–induced ulcers recur o Chronic infection with H pylori weakens natural defenses of stomach lining against acid

 Agents that eradicate H pylori (antimicrobials), neutralize stomach acid (antacids), and reduce stomach acid output (H2 blockers, PPIs) are now used in combination regimens Marc Imhotep Cray, M.D.

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Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

Etiology and Pathogenesis of Helicobacter pylori

â&#x20AC;ŚIllustration continues do on next slideâ&#x20AC;Ś

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Etiology and Pathogenesis of H pylori cont.

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

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Treatment of H pylori Infection cont. Currently, triple therapy consisting of a PPI combined with amoxicillin (metronidazole may be used in penicillin-allergic patients) plus clarithromycin is therapy of choice Quadruple therapy of bismuth subsalicylate, metronidazole, and tetracycline plus a PPI is another option  Quadruple therapy should be considered in areas w high 

resistance to clarithromycin Acid suppression by PPI in conjunction with antibiotics alleviates ulcer related symptoms (eg, abdominal pain, nausea), heals gastric mucosal inflammation, and enhances efficacy of antibiotics against H pylori at gastric mucosal surface

NB: Tetracycline(s) contraindicated in children younger than 12 years permanent discoloration of teeth and inhibition of bone growth. Marc Imhotep Cray, M.D.

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Diagnosis and Management of H pylori

Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

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Tests for Helicobacter pylori

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. Marc Imhotep Cray, M.D.

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Peptic Ulcer Treatment  Agents Used Antacids, PPIs, H2 blockers, muscarinic antagonists (M1 blockers), and prostaglandin E2 analog (misoprostol) MOAs  PPIs (eg, Omeprazole (Prilosec), lansoprazole (Prevacid), and esomeprazole (Nexium) bind irreversibly to and inactivate H+,K+-ATPase pump which blocks acid secretion until more pumps are synthesized Use  very effective and generally well tolerated  firstline for Tx of both Peptic Ulcers & GERD Drug-drug interactions  Omeprazole is a cytochrome P-450 inhibitor, thus can cause inc. bld levels of agents metabolized by CYP-450 system  Omeprazole may decrease efficacy of clopidogrel b/c it inhibits conversion to its active form reducing anti-platelet activity Marc Imhotep Cray, M.D.

Adverse Effects of PPIs Common AEs  headache, dizziness, nausea, diarrhea, constipation  Prolonged use can lead to bacterial overgrowth in GI tract clostridia difficile colitis  Omeprazole can cause thrombocytopenia, whereas esomeprazole does not carry the same risk of lowering platelets Uncommon AEs  Recent analysis indicate people (age > 50) taking high doses of PPIs for more than a year 2.6 times as likely to break a hip vs people not taking PPIs particularly ↑ risk of osteoporosisrelated bone fractures o H2-receptor inhibitors also ↑ fracture risk but not to extent as did PPIs Marc Imhotep Cray, M.D.

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Peptic Ulcer Treatment cont.  Histamine stimulates acid secretion by activating H2 receptors so H2 receptor blockers (eg, cimetidine) reduce acid levels AEs are allergic reactions;  cimetidine inhibit hepatic CYP-450 system substrates anti-epileptics, theophylline, warfarin, OCPs  antiandrogen activity, impotence, increase prolactin gynecomastia & galactorrhea  ranitidine, famotidine more potent & longer duration of action, no antiandrogen or increase prolactin Note: Fexofenadine, a histamine H1 receptor Marc Imhotep Cray, M.D.

antagonist and other H1 blockers have NO AFFECT ON ACID SECRETION

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Peptic Ulcer Treatment cont.  Misoprostol (PGE1 analog) stimulates mucous secretion which protects GI endothelial cells from high acid levels   

used for NSAID induced ulcers and prevention in persons on NSAIDs AEs Abd pain, diarrhea, vaginal spotting and dysmenorrhea Contraindicated in pregnancy or planned preg.=abortifacient

 Sucralfate (sucrose-sulfate-aluminum hydroxide)[cytoprotective] stimulates bicarbonate, mucus, & prostaglandin secretion 

should not be coadministered w, PPIs, H2 antagonists or antacids b/c acid is required for sucralfate to work

 ACh activates M1 receptors to stimulate acid release M1 blockers (eg, Dicyclomine) block this action and reduce GI acid levels Marc Imhotep Cray, M.D.

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Prostaglandins (PGE2 & PGI2)  Locally produced PGs E2 & I2 inhibit parietal cell acid secretion  PGs are produced by cyclooxygenase enzyme 

In stomach, PGs are produced by constitutively expressed COX-1 enzyme isoform

 Mucosal protective mechanisms  mucus and bicarbonate is secreted by cells in gastric and duodenal mucosa and provides a protective relatively alkaline physical barrier against otherwise destructive intragastric environment o mucus and bicarb. secretion promoted by prostaglandins (PGE) o PGE also inhibit gastric acid secretion Remember Misoprostol (synthetic analog of protective PGE1)  has same antisecretory and cytoprotective properties PGs E2 & I2. Traditionally coadministered w NSAIDs to counteract latter’s effects on endogenous prostaglandin synthesis thus preventing NSAID-induced bleeding. Marc Imhotep Cray, M.D.

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COX-2 Inhibitors  Celecoxib, rofecoxib, and valdecoxib COX-2 inhibitors, reduce inflammation and pain in a manner similar to aspirin and ibuprofen w lower gastric irritation MOA Reversibly and selectively inhibits cyclooxygenase (COX) isoform 2 found in inflammatory cells and vascular endothelium  mediates inflammation and pain  spares COX-1 helps maintain gastric mucosa thus does not have corrosive effects of other NSAIDs on GI lining AEs CV risk of COX-2 Inhibitors may mitigate advantage  For example, valdecoxib and rofecoxib removed from U.S. market due to an increased risk of MI and CVA Marc Imhotep Cray, M.D.

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PUD Tx: Medications Site of Action ď ąAgents can be divided into drugs that: 1. 2. 3. 4.

decrease acid secretion neutralize acid promote mucosal defense modify risk factors

ď ąH. pylori infection is an important contributing factor in pathogenesis of peptic ulcer disease

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

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Acid suppression therapy

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Le T, Bhushan V. First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Education, 2017.

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Acid suppression therapy (2)

Review molecular control of parietal cell acid HCl secretion, slides 57 to 62.

 H2 receptor antagonists (H2 blockers) inhibit activation of histamine H2 receptor by endogenous histamine  Muscarinic antagonists inhibit signaling through M3 muscarinic ACh receptor  Proton pump inhibitors decrease activity of H+/K+ATPase on of parietal cell  Antacids neutralize acid in stomach lumen  Coating agents provide a protective layer on epithelial surface of gastric mucosa  Bismuth & antibiotics act to eradicate H. pylori from mucus layer coating gastric mucosa Marc Imhotep Cray, M.D.

Golan DE, Tashjian AH (Eds.) Principles of Pharmacology : The Pathophysiologic 1462012. Basis of Drug Therapy, 3rd Ed. Philadelphia, PA: Wolters Kluwer-LWW,

Gastroesophageal Reflux Disease (GERD) Also see GI Pharm Tutorial 2, Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease

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Gastroesophageal Reflux Disease Overview  In GERD, stomach acids move back into esophagus called reflux  Esophagus moves swallowed food into stomach via peristalsis 

Reflux occurs when muscles fail to prevent acid from moving backward

 Starch, fat, and protein in food are broken down by HCl and enzymes (pepsin) 

mucous lining of stomach protects it from acid and enzymes but esophageal lining offers only weak resistance to these substances

 GERD symptoms are usually short lived and infrequent but chronic in approx. 20% of cases Marc Imhotep Cray, M.D.

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GERD Overview cont.  Esophagitis occurs when acid causes irritation or Inflammation extensive esophageal damage and injury lead to erosive esophagitis  GERD symptoms can occur with no signs of esophageal inflammation or injury (nonerosive esophageal reflux disease, or NERD), but patients have some GERD symptoms (burning sensations behind breastbone=“heartburn”)  Nerves near endothelial lining are exposed to acid, and pain results Note: H pylori Infection is not associated with GERD, thus antibiotics have no place management. Marc Imhotep Cray, M.D.

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GERD Overview cont. Pathophysiology  Excessive or inappropriate relaxation of LOS results in GERD, esophagitis and esophageal ulceration stricturing resulting in mechanical obstruction and sometimes a secondary esophageal dysmotility & spasm 

Reduced esophageal clearance of acid may also contribute

 acid reflux triggers columnar metaplasia of native squamous epithelium (known as Barrett’s esophagus) Barrett’s esophagus is a pre-malignant condition for esophageal adenocarcinoma (lower 1/3) Note: Esophageal Ca upper 1/3 is squamous cell risk factors are EtOH and smoking Marc Imhotep Cray, M.D.

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Complications of Peptic Reflux (Esophagitis and Stricture)

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Complications of Peptic Reflux (esophagitis and stricture) cont.

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GERD Treatment  Proton pump inhibitors reduce acid reflux by blocking expulsion of hydrogen ions by proton pumps  Prototype omeprazole  Newer oral PPIs include lansoprazole, esomeprazole, and rabeprazole but they do not cure condition o Even when drugs relieves Sx completely, condition usually recurs within months after drugs discontinued • Chronic cases require treatment for life

 Goals in treating GERD  To eliminate symptoms; heal esophagitis; prevent relapse of esophagitis; prevent development of complications Marc Imhotep Cray, M.D.

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Symptoms and Medical Management of Sliding Esophageal Hiatus Hernia

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Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 154

Principles of medical management

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Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

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Pancreatitis

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Treatment of Pancreatitis  Pancreatitis is acute or chronic inflammation of pancreas which secretes digestive enzymes into small intestine (for fat, protein, and carbohydrate digestion) and insulin and glucagon into blood (for glucose regulation)  Acute pancreatitis is sudden and brief and caused by gallstones or excessive alcohol consumption  Dyspnea and hypoxia are common  Treatment of acute pancreatitis includes use of IV fluids, pain meds, oxygen, antibiotics (eg, imipenem-cilastatin), or surgery Marc Imhotep Cray, M.D.

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Acute Pancreatitis

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Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

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Chronic (Relapsing) Pancreatitis  Chronic pancreatitis may develop if pancreatic injury continues caused by digestive enzymes attacking and destroying pancreatic tissue (pancreatic calcifications on x-ray= hallmark)  Prolonged alcohol abuse is a common cause, but chronic form may occur after only 1 acute attack, esp. if a pt. has damaged pancreatic ducts, CF, hypercalcemia, or hyperlipidemia  Chronic pancreatitis therapy includes use of antiinflammatory agents, a high-carbohydrate, low-fat diet, and protease pancreatic enzyme supplements  Can also result in diabetes mellitus and require insulin therapy Marc Imhotep Cray, M.D.

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Chronic (Relapsing) Pancreatitis

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Gallstones (Cholelithiasis)

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Pathologic Features of Gallstones Gallstones develop in gallbladder from crystals of cholesterol or bilirubin  Presence of gallstones is called cholelithiasis Stones can be too small to be seen with eye (biliary sludge) or can be the size of golf balls There may be 1 or hundreds of stones Obstruction by gallstones of cystic duct (that leads from gallbladder to common bile duct) causes pain (biliary colic), infection, and inflammation (cholecystitis) Marc Imhotep Cray, M.D.

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Features of Gallstones cont.  Gallstone disease affects 10% to 15% of US population but only 1% to 3% report symptoms in a given year  Women, particularly during pregnancy, are at increased risk b/c estrogen stimulates liver to remove more cholesterol from blood and divert it into bile Management  Avoidance of fatty meals or nonsurgical approaches are used only in special situations (when a serious medical condition prevents surgery and for cholesterol stones) 

Stones usually recur after nonsurgical intervention

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Cholelithiasis Facts about gallstones  Most common biliary tract disease:  High prevalence: 10% to 20% of males & 30% to 40% of FM are affected  Two types can be recognized macroscopically and by biochemical analysis: o Cholesterol stones (80%) o Pigmentary bilirubin stones (20%) Marc Imhotep Cray, M.D.

Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014.

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Gallbladder with stones: gross and radiograph

Fox SI. Human Physiology 12th ed. New York, NY: McGraw-Hill, 2011.

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Pathogenesis of Gallstones

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Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 2014. 166

Formation of gallstones

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Hall JE. Guyton and Hall Textbook of Medical Physiology, 13th ed. Philadelphia, PA: Elsevier, 2016.

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Risk factors for cholesterol gallstones Risk factors include six Fs:      

Female Forty and above Fertile (multiparous) Fat Flatulent (intestinal disease or malabsorption) Familial, including high prevalence in some ethnic groups (e.g., Native Americans)

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Predisposing Factors

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Gallstone Treatment  Using drugs synthesized from bile acid to dissolve gallstones is known as oral dissolution therapy  Ursodiol and chenodiol work best for small cholesterol stones o Months of treatment may be necessary before all stones dissolve

 AEs Both drugs cause mild diarrhea, and o chenodiol may increase blood cholesterol levels and increase activity of transaminase (hepatic enzymes=AST &ALT)

 Contact dissolution therapy is an experimental procedure that involves injecting a drug directly into gallbladder to dissolve stones Marc Imhotep Cray, M.D.

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Gallstone Treatment cont.  Drug methyl-tert-butyl ether can dissolve some stones in 1 to 3 days, but it must be used carefully b/c it is a flammable and toxic anesthetic

 Extracorporeal shock wave lithotripsy (ESWL) is use of shock waves to disintegrate stones into tiny pieces that can pass through bile ducts without causing blockage  Attacks of biliary colic (intense pain) are common after treatment, and success rate of ESWL is unknown

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Liver Physiology and Pathology See Cirrhosis of the Liver and Portal Hypertension_Tutorial 1 and ICM_ Systems-based Pathophysiologic High Yield Cases, CASE 68

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Liver Anatomy  Structural units of liver liver lobules  Functional units of liver liver acinus  How are these liver acini defined?  A collection of hepatocytes that receive a blood supply from same arteriole and are drained by same venule

 What is unique about the liver’s blood supply?  It receives some oxygenated blood and some deoxygenated blood o Oxygenated blood coming from hepatic artery off of celiac axis o Deoxygenated component coming from portal circulation Marc Imhotep Cray, M.D.

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Schematic of microscopic appearance of liver Illustration description: (a) Hepatic lobules are structural-functional units of liver (b) A small section of liver showing location of bile canaliculi and ducts with respect to blood and liver cells (hepatocytes)  Hepatic portal veins communicate with hepatic sinusoids and bring absorbed substances to liver from small intestines  Hepatocytes take up and process nutrients and other factors from hepatic sinusoids  Bile (green) is formed by uptake by hepatocytes of bile salts and secretion into bile canaliculi  Finally, central veins, located at center of each lobule, drain blood from lobules into systemic venous circulation Marc Imhotep Cray, M.D.

Widmaier EP, Raff H, Strang KT. Vander’s Human Physiology: The Mechanisms of Body Function, 14th Ed. New York, NY: McGraw-Hill Education, 2016. 174

Liver Function  Liver creates, regulates, stores, and secretes substances used by GI system bile being major digestive chemical synthesized   

During a meal, bile is secreted by liver cells and moves through hepatic duct system into small intestine used to break down fat molecules Between meals, gallbladder stores bile Bile serves as a waste disposal system for toxins removed from blood by liver

 Liver plays a major role in regulation of blood glucose  Liver also synthesizes, dissolves, and stores amino acids, protein, and fat, and it stores several important vitamins (B12 and A) Marc Imhotep Cray, M.D.

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Liver Function cont.  Liver disposes of cellular waste and decomposes toxic substances such as alcohol w disposal occurring via bile  b/c liver clears toxins, hepatocytes are organized for optimal contact with sinusoids (leading to and from blood vessels) and bile ducts

 Liver is unique in that it can regenerate, but this capacity can be exceeded Marc Imhotep Cray, M.D. by extensive damage

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Liver Function cont.  Primary Fx is digestive to produce and secrete bile  Other functions o Carbohydrate metabolism o Cholesterol metabolism o Fat metabolism o Amino acid and protein synthesis o Storage of fat soluble vitamins o Vitamin B12, A, iron and copper o Immune functions o Detoxification and biotransformation

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Raffa RB. Netter's Illustrated Pharmacology, Updated Ed. Philadelphia, PA: Elsevier, 177 2014.

Bilirubin Production and Excretion  Hemoglobin is degraded to bilirubin by reticuloendothelial system(RES) (unconjugated or indirect)  Hepatocytes sequester bilirubin, conjugate it with glucuronic acid, and excrete it into bile o

Intestinal bacteria convert conjugated (direct) bilirubin into urobilinogen which is returned to liver and bile or excreted by kidneys

 Bilirubin assay is used to determine liver (jaundice) or gallbladder dysfunction  Jaundice occurs, as a result of liver disease or bile duct blockage or when red blood cells are broken down too fast for liver to process

Direct bilirubin—conjugated with glucuronic acid; water soluble. Indirect bilirubin—unconjugated; water insoluble

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Bilirubin Production and Excretion cont.  Hemoglobin is degraded to bilirubin by reticuloendothelial system(RES)=Macrophages  Bilirubin is carried in the circulation bound to albumin  In liver, bilirubin is conjugated with glucuronic acid via enzyme UDP glucuronyl transferase  A portion of conjugated bilirubin is excreted in urine and a portion is secreted into bile In intestine, conjugated bilirubin is converted to urobilinogen which is returned to liver via enterohepatic circulation, and urobilin and stercobilin, which are excreted in feces (gives stool its brown color) Marc Imhotep Cray, M.D.

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Bilirubin Production and Excretion

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Types and Causes of Hyperbilirubinemia  Unconjugated (indirect) hyperbilirubinemia (pre-hepatic)  Hemolytic, physiologic (newborns), Crigler-Najjar, Gilbert syndrome

 Conjugated (direct) hyperbilirubinemia (post-hepatic)  Biliary tract obstruction: gallstones, cholangiocarcinoma, pancreatic or liver cancer, liver fluke  Biliary tract disease: o 1° sclerosing cholangitis o 1° biliary cholangitis  Excretion defect: Dubin-Johnson syndrome, Rotor syndrome

 Mixed (direct and indirect) hyperbilirubinemia (intra-hepatic)  Hepatitis, cirrhosis

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NB: Only direct & total bilirubin can be measured, indirect (unconjugated bilirubin) is calculated as difference betw. total and direct bilirubin.

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Jaundice  Abnormal yellowing of the skin and/or sclera due to bilirubin deposition Hyperbilirubinemia 2° to ↑ production or↓ disposition (impaired hepatic uptake, conjugation, excretion)  Common causes of ↑ levels of bilirubin: Remember HOT Liver Hemolysis Obstruction Tumor Liver disease Marc Imhotep Cray, M.D.

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Physiologic neonatal jaundice  At birth, immature UDP-glucuronosyltransferase  unconjugated hyperbilirubinemia  jaundice/ kernicterus (deposition of unconjugated, lipid-soluble bilirubin in brain, particularly basal ganglia)  Occurs after first 24 hours of life and usually resolves without treatment in 1–2 weeks  Treatment: phototherapy (non-UV) isomerizes unconjugated bilirubin to water-soluble form Marc Imhotep Cray, M.D.

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Cirrhosis of the Liver Also see: Cirrhosis of the Liver and Portal Hypertension_Tutorial 1

 In cirrhosis, widespread nodules in liver combined with fibrosis distort normal liver architecture, which interferes with blood flow through organ  lead to inability of liver to perform biochemical functions

 Most common cause is alcoholic liver disease, others are       

chronic viral hepatitis B, C, and D chronic autoimmune hepatitis inherited metabolic diseases (hemochromatosis, Wilson disease) bile duct diseases chronic congestive heart failure parasitic infections (schistosomiasis) and long-term exposure to toxins or drugs

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Cirrhosis cont.  Cirrhosis is irreversible, but treatment of underlying liver disease may slow its progression  Cessation of alcohol intake stops progress of alcoholic cirrhosis  Stopping a hepatotoxic drug or removal of an environmental toxin also halts disease progression  Interferon is used to treat viral hepatitis B and C  Prednisone and azathioprine used to treat autoimmune hepatitis  Drugs such as ursodiol may help in primary biliary cirrhosis Marc Imhotep Cray, M.D.

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Nausea and Vomiting (Chemotherapy-induced)

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Summary of drugs used to treat chemotherapyinduced nausea and vomiting (CINV)(CIE & RIE) PHENOTHIAZINES Prochlorperazine COMPAZINE 5-HT3 SEROTONIN RECEPTOR BLOCKERS Dolasetron ANZEMET Granisetron KYTRIL Ondansetron ZOFRAN Palonosetron ALOXI SUBSTITUTED BENZAMIDES Metoclopramide REGLAN BUTYROPHENONES Droperidol Haloperidol HALDOL Marc Imhotep Cray, M.D.

BENZODIAZEPINES Alprazolam XANAX Lorazepam ATIVAN CORTICOSTEROIDS Dexamethasone DECADRON Methylprednisolone MEDROL SUBSTANCE P/NEUROKININ-1 RECEPTOR BLOCKER Aprepitant EMEND

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Physiology of Emesis  Emesis is expulsion of undigested food through mouth  Nausea, state preceding vomiting, sensation of needing to vomit  Emesis is caused by allergy, food, anticancer drugs (eg, cisplatin), hepatitis, stress, and pregnancy  Central neural vomiting regulation is located in medulla 

Two areas=Chemoreceptor trigger zone and Vomiting center

 Chemoreceptor trigger zone (CTZ), in area postrema on floor of IV ventricle, is quite sensitive to chemicals 

Blood-brain barrier (BBB) is poorly developed in CTZ (accessible to emetic agents in circulation)

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Physiology of Emesis cont. ď ą Vomiting center (VC) integrates emetic response and is located in dorsolateral border of medullar reticular formation (includes nucleus tractus solitarius, parvicellular reticular formation, and visceral and somatic motor nuclei)

ď&#x201A;§ VC gets excitatory inputs from nerve endings of o vagal sensory fibers in GI tract o vestibular nuclei o higher centers in cortex (vomiting induced by disgust) o CTZ o intracranial pressure receptors

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Basis of Pharmacotherapy ď ą Pharmacologic intervention relies on inhibition of inputs or depression of the vomiting center (VC) ď&#x201A;§

Mechanisms controlling vomiting and sites of action of anti-emetics.

Vomiting center receives inputs from several sources: o Area postrema (CTZ) o Vestibular apparatus o Peripheral afferents from pharynx, GI tract, and genitals o Higher cortical centers Griffiths M. Crash Course: Gastrointestinal System, 4th Ed. London: Elsevier, 2012.

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Antiemetics  Antiemetics are useful in treatment of vomiting assoc. with motion sickness, chemotherapy-induced emesis (CIE), radiation-induced emesis (RIE), postoperative nausea and vomiting (PONY), and other causes There are several classes of antiemetic drugs  H1 antagonists (eg, dimenhydrinate, clizines, diphenhydramine, hydroxyzine) block H1 receptors in midbrain to relieve histamine-induced emesis  Most H1 blockers have additional anticholinergic action  AE include drowsiness and loss of coordination o Newer histamine blockers (2nd generation agents) are not useful for vomiting b/c they cannot penetrate blood-brain barrier= no drowsiness and loss of coordination Marc Imhotep Cray, M.D.

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Antiemetics cont.  Dopamine antagonists (eg, metoclopramide, domperidone, chlorpromazine, droperidol) are usually used as antipsychotic drugs but can suppress emesis by blocking D2 receptors in area postrema and CTZ 

Metoclopramide also a prokinetic (see slide 192)

 Benzodiazepines (eg, diazepam, lorazepam) are useful for anticipatory nausea and vomiting before cancer therapy  

They are also used for vestibular disorders (vertigo, dizziness, nystagmus) Caution Ethanol combined w BDZs, particularly at high doses, may produce unconsciousness, respiratory depression, and even death

 Muscarinic receptor antagonists have also been used (scopolamine is no longer available for this use in U.S.)  relieve emesis by blocking M1 receptors in vestibular nuclei Marc Imhotep Cray, M.D.

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In Re of Scopolamine Ability of scopolamine to prevent motion-induced nausea via inhibition of vestibular input to CNS results in inhibition of vomiting reflex  Also has direct action on vomiting center within reticular formation of brain stem

AEs Most common are dry mouth, drowsiness, transient impairment of accommodation including mydriasis and blurred vision infrequent, especially in higher-than-therapeutic doses, include disorientation, memory disturbances, dizziness, restlessness, hallucinations, confusion, difficulty urinating, rashes or erythema, acute narrow-angle glaucoma, dry, itchy, or red eyes Marc Imhotep Cray, M.D.

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Metoclopramide (also a prokinetic agent) MOA  Enhances gastric motility without stimulating gastric secretions  Augments cholinergic release of ACh from postganglionics, sensitizing muscarinic receptors on smooth muscle cells  Blocks dopamine D2 and 5-HT3 receptors (antiemetic action) Uses & clinical effects  GERD= reduced reflux and increased gastric emptying due to decrease of resting tone of lower esophageal sphincter  Nausea and vomiting = antiemetic effect produced by blockade of dopamine D2 receptors in CTZ  Gastroparesis= promotion of motility Adverse effects extrapyramidal or dystonic reactions Marc Imhotep Cray, M.D.

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Chemotherapy-induced nausea and vomiting (CINV)

Comparison of emetic potential of anticancer drugs.

 Nausea and vomiting produced by chemotherapeutic agents demands especially effective management 

Nearly 70% to 80% of patients who undergo chemotherapy experience nausea and/or vomiting

 Several factors influence incidence and severity of CINV, including specific chemotherapeutic drug (Fig) dose, route, and schedule of administration, and patient variables Marc Imhotep Cray, M.D.

Whalen K. (Ed.) Lippincott Illustrated Reviews, Pharmacology 6th Ed. WKH-LWW 2014. 195

CINV cont.  Young patients and women are more susceptible CINV than older patients and men  10% to 40% of patients experience nausea and/or vomiting in anticipation of chemotherapy (anticipatory vomiting)  CINV not only affects quality of life but  can also lead to rejection of potentially curative chemotherapy  Uncontrolled vomiting can produce dehydration, profound metabolic imbalances, and nutrient depletion Marc Imhotep Cray, M.D.

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CINV cont. 5-HT3 receptor blockers: include ondansetron, granisetron, and palonosetron  MOA selectively block 5-HT3 receptors in periphery (visceral vagal afferent fibers) and in brain (CTZ)  This class of agents= DOC in treating CINV largely b/c of longer duration of action and superior efficacy

Efficacy of antiemetic drugs.

Whalen K. (Ed.) Lippincott Illustrated Reviews, Pharmacology 6th Ed. WKH-LWW 2014. Marc Imhotep Cray, M.D.

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CINV cont.  Palonosetron is a 5-HT3 antagonist that is effective against drugs with high emetogenic activity, such as cisplatin  Dolasetron has a propensity to affect heart and thus makes it a poor choice for patient’s w heart disease  Electrocardiographic changes, such as a prolonged QTc interval, can occur with dolasetron and high doses of ondansetron for this reason, dolasetron is no longer approved for CINV prophylaxis

Butyrophenone  Droperidol also affects the heart and now is generally a second-line drug used in combination with opioids or benzodiazepines Marc Imhotep Cray, M.D.

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CINV cont. Corticosteroids: dexamethasone and methylprednisolone, used alone, are effective against mildly to moderately emetogenic chemotherapy  Most frequently, they are used in combination with other agents  Antiemetic MOA is not known it may involve blockade of prostaglandins  Combination regimens: Antiemetic drugs are often combined to increase antiemetic activity or decrease toxicity Marc Imhotep Cray, M.D.

Effectiveness of antiemetic activity of some drug combinations against emetic episodes in first 24 hours after cisplatin chemotherapy.

Whalen K. (Ed.) Lippincott Illustrated Reviews, Pharmacology 6th Ed. WKH-LWW 2014. 199

CINV cont. Substance P/neurokinin-1 receptor blocker: aprepitant targets neurokinin receptor in brain and blocks actions of natural substance  Aprepitant is indicated only for highly or moderately emetogenic chemotherapy regimens  Aprepitant usually administered orally with dexamethasone and a 5-HT3 antagonist

 PK & drug-drug interactions Aprepitant undergoes extensive phase I metabolism- by CYP3A4- and it may slow metabolism of other drugs metabolized by this enzyme warfarin and oral contraceptives Marc Imhotep Cray, M.D.

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Emesis & Antiemetic Capsule  Antiemetics antagonize D2 and 5HT3 Receptors in chemoreceptor trigger zone (CTZ) of brain to prevent vomiting  CTZ chemoreceptors sense chemical stimuli, whereas actual act of vomiting is controlled by medulla

Classes of Medications Used:  Anticholinergic drugs (scopolamine) and  H1-antagonists (meclizine [Antivert], dimenhydrinate [Dramamine]) prevent motion sickness but do not prevent stimulation of CTZ

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Emesis & Antiemetic Capsule cont.  Several drugs are used to control chemotherapy-induced nausea and vomiting:  D2 dopamine receptor antagonists include prochlorperazine (Compazine), metoclopramide (Reglan), and droperidol (Inapsine) o AEs droperidol is assoc. w prolonged QT and torsades de pointes

 Odansetron (Zofran) is a 5HT3 serotonin receptor antagonist DOC for potent ChemoTx agent induced N/V  Cannabinoids like dronabinol (Marinol) work by an unknown mechanism and are not commonly used  Aprepitant (Emend) blocks neurokinin receptors in CTZ Marc Imhotep Cray, M.D.

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THE END

See next slide for hypermedia to further study tools and resources. Marc Imhotep Cray, M.D.

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Further study tools and resources:  e-Learning resource center: IVMS Medical Pharmacology Cloud Folder  IVMS Online Medical Pharmacology Course: (5 interactive and looping components.) Instructor: Marc Imhotep Cray, M.D.

Course Website: Link

1. Integrated Scientific and Clinical Pharmacology: A Course Syllabus and Digital

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