Pathophysiology of Gastrointestinal System Diseases PDF

Pathophysiology of Gastrointestinal System Diseases  Learning Objectives: ► Nausea and vomiting ► Diarrhea, ► Constipation ► Gastroesophageal reflux disease (GERD) ► Gastritis ► Peptic Ulcer ► Inflammatory Bowel Diseases: -- Ulcerative Colitis, -- Crohn Disea...

Pathophysiology of Gastrointestinal System Diseases  Learning Objectives: ► Nausea and vomiting ► Diarrhea, ► Constipation ► Gastroesophageal reflux disease (GERD) ► Gastritis ► Peptic Ulcer ► Inflammatory Bowel Diseases: -- Ulcerative Colitis, -- Crohn Disease  Nausea and vomiting ► Nausea is usually defined as the inclination to vomit or as a feeling in the throat or epigastric region alerting an individual that vomiting is imminent. ► Vomiting is defined as the ejection or expulsion of gastric contents through the mouth and is often a forceful event. ► Nausea and/or vomiting is often a part of the symptom complex for a variety of gastrointestinal, cardiovascular, infectious, neurologic, metabolic, or psychogenic processes. ► The three consecutive phases of emesis include: ► nausea, ► retching, and ► vomiting. ► Nausea, the imminent need to vomit, is associated with gastric stasis and may be considered a separate and singular symptom. ► Retching is the labored movement of abdominal and thoracic muscles before vomiting. ► The final phase of emesis is vomiting, the forceful expulsion of gastric contents caused by GI retroperistalsis. ► The act of vomiting requires the coordinated contractions of the abdominal muscles, pylorus, and antrum, a raised gastric cardia, diminished lower esophageal sphincter pressure, and esophageal dilatation ► Vomiting is triggered by afferent impulses to the vomiting center, a nucleus of cells in the medulla. ► Impulses are received from sensory centers, which include the chemoreceptor trigger zone (CTZ), cerebral cortex, and visceral afferents from the pharynx and GI tract. These afferent impulses are integrated by the vomiting center, resulting in efferent impulses to the salivation center, respiratory center, and the pharyngeal, GI, and abdominal muscles, leading to vomiting. Steps of Vomiting 6 treatment ► 5-Hydroxytryptamine-3 Receptor Antagonists: dolasetron,granisetron, ondansetron, and palonosetron ► 5-HT3-RAs block presynaptic serotonin receptors on sensory vagal fibers in the gut wall, effectively blocking the acute phase of chemotherapy-induced nausea and vomiting (CINV) ► Metoclopramide ► Metoclopramide, a procainamide, provides significant antiemetic effects by blocking the dopaminergic receptors centrally in the CTZ. ► Metoclopramide increases lower esophageal sphincter tone, aids gastric emptying, and accelerates transit through the small bowel, possibly through the release of acetylcholine. ► Antihistamine–Anticholinergic Drugs: ► Cyclizine (Marezine), Dimenhydrinate (Dramamine), Diphenhydramine (Benadryl) ► Antiemetic drugs from the antihistaminic–anticholinergic category appear to interrupt various visceral afferent pathways that stimulate nausea and vomiting and may be appropriate in the treatment of simple nausea and vomiting. ► Adverse reactions associated with the use of the antihistaminic–anticholinergic agents primarily include drowsiness, confusion, blurred vision, dry mouth, and urinary retention, and possibly tachycardia, particularly in elderly patients. Diarrhea ► Diarrhea is an increased frequency and decreased consistency of fecal discharge as compared to an individual's normal bowel pattern. ► Diarrhea is caused by many viral and bacterial organisms. It is most often a minor discomfort, not life threatening, and usually self-limited. ► Diarrhea may be associated with a specific disease of the intestines or secondary to a disease outside the intestines. For instance, bacillary dysentery directly affects the gut, whereas diabetes mellitus causes neuropathic diarrheal episodes. ► Infectious diarrhea is often acute; diabetic diarrhea is chronic. ► Four general pathophysiologic mechanisms disrupt water and electrolyte balance, leading to diarrhea, and are the basis of diagnosis and therapy. ► These are: ► (a) a change in active ion transport by either decreased sodium absorption or increased chloride secretion; ► (b) change in intestinal motility; ► (c) increase in luminal osmolarity; and ► (d) increase in tissue hydrostatic pressure. ► These mechanisms have been related to four broad clinical diarrheal groups: secretory, osmotic, exudative, and altered intestinal transit.  Clinical Presentation of Diarrhea General: Usually, acute diarrheal episodes subside within 72 hours of onset, whereas chronic diarrhea involves frequent attacks over extended time periods. Signs and symptoms: Abrupt onset of nausea, vomiting, abdominal pain, headache, fever, chills, and malaise. Bowel movements are frequent and never bloody, and diarrhea lasts 12 to 60 hours. Intermittent periumbilical or lower right quadrant pain with cramps and audible bowel sounds is characteristic of small intestinal disease. When pain is present in large-intestinal diarrhea, it is a gripping, aching sensation with tenesmus (straining, ineffective, and painful stooling). Pain localizes to the hypogastric region, right or left lower quadrant, or sacral region. In chronic diarrhea, a history of previous bouts, weight loss, anorexia, and chronic weakness are important findings. Physical examination: Typically demonstrates hyperperistalsis with borborygmi and generalized or local tenderness. Laboratory tests: Stool analysis studies include examination for microorganisms, blood, mucus, fat, osmolality, pH, electrolyte and mineral concentration, and cultures. Stool test kits are useful for detecting gastrointestinal viruses, particularly rotavirus. Antibody serologic testing shows rising titers over a 3- to 6-day period, but this test is not practical and is nonspecific. Occasionally, total daily stool volume is also determined. Direct endoscopic visualization and biopsy of the colon may be undertaken to assess for the presence of conditions such as colitis or cancer. Radiographic studies are helpful in neoplastic and inflammatory conditions.  Drugs Causing Diarrhea Laxatives Cholinergics Antacids containing magnesium Bethanechol Antineoplastics Neostigmine Auranofin (gold salt) Antibiotics Cardiac agents Clindamycin Quinidine Tetracyclines Digitalis Sulfonamides Any broad-spectrum antibiotic Digoxin Antihypertensives Nonsteroidal antiinflammatory drugs Reserpine Guanethidine Misoprostol Methyldopa Colchicine Guanabenz Proton pump inhibitors Guanadrel Angiotensin-converting enzyme inhibitors H2-receptor blockers Recommendations for treating acute diarrhea. Follow these steps: (a) Perform a complete history and physical examination. (b) Is the diarrhea acute or chronic? If chronic diarrhea, go to Figure 43–2. (c) If acute diarrhea, check for fever and/or systemic signs and symptoms (i.e., toxic patient). If systemic illness (fever, anorexia, or volume depletion), check for an infectious source. If positive for infectious diarrhea, use appropriate antibiotic/anthelmintic drug and symptomatic therapy. If negative for infectious cause, use only symptomatic treatment. (d) If no systemic findings, then use symptomatic therapy based on severity of volume depletion, oral or parenteral fluid/electrolytes, antidiarrheal agents , and diet. (RBC, red blood cells; WBC, white blood cells.) Recommendations for treating chronic diarrhea. Follow these steps: (a) Perform a careful history and physical examination. (b) The possible causes of chronic diarrhea are many. These can be classified into intestinal infections (bacterial or protozoal), inflammatory disease (Crohn disease or ulcerative colitis), malabsorption (lactose intolerance), secretory hormonal tumor (intestinal carcinoid tumor or vasoactive intestinal peptide-secreting tumor [VIPoma]), drug (antacid), factitious (laxative abuse), or motility disturbance (diabetes mellitus, irritable bowel syndrome, or hyperthyroidism). (c) If the diagnosis is uncertain, selected appropriate diagnostic studies should be ordered. (d) Once diagnosed, treatment is planned for the underlying cause with symptomatic antidiarrheal therapy. (e) If no specific cause can be identified, symptomatic therapy is prescribed. (RBC, red blood cells; WBC, white blood cells.) Nonpharmacologic Management ► Dietary management is a first priority in the treatment of diarrhea. ► Water and Electrolytes ► Rehydration and maintenance of water and electrolytes are primary treatment goals until the diarrheal episode ends. ► If the patient is volume depleted, rehydration should be directed at replacing water and electrolytes to normal body composition. ► Then water and electrolyte composition are maintained by replacing losses.  Oral Rehydration Solutions a World Health Organization reduced osmolarity Oral Rehydration Solution. b Carbohydrate is glucose. c Rice syrup solids are carbohydrate source. a b Rehydralyteb (Ros Enfalyte (Mead WHO-ORS Pedialyte (Ross) Resolb (Wyeth) s) Johnson) Osmolality 245 249 304 200 269 (mOsm/L) Carbohydratesb (g/ 13.5 25 25 30c 20 L) Calories (cal/L) 65 100 100 126 80 Electrolytes (mEq/L) Sodium 75 45 75 50 50 Potassium 20 20 20 25 20 Chloride 65 35 65 45 50 Citrate — 30 30 34 34 Bicarbonate 30 — — — — Calcium — — — — 4 Magnesium — — — — 4 Sulfate — — — — — Phosphate — — — — 5  Pharmacologic treatment ► Opiates and Their Derivatives ► Opiates and opioid derivatives ► (a) delay the transit of intraluminal contents or ► (b) increase gut capacity, prolonging contact and absorption. ► Enkephalins, which are endogenous opioid substances, regulate fluid movement across the mucosa by stimulating absorptive processes. ► Loperamide is antisecretory; it inhibits the calcium-binding protein calmodulin, controlling chloride secretion. ► Loperamide can be used in traveler's diarrhea. ► Antisecretory Agents ► Bismuth subsalicylate appears to have antisecretory, antiinflammatory, and antibacterial effects. ► As a nonprescription product, ► it is marketed for indigestion, relieving abdominal cramps, and controlling diarrhea, including traveler's diarrhea. ► Miscellaneous Products ► Probiotics are microorganisms that have been used for many years to replace colonic microflora. This supposedly restores normal intestinal function and suppresses the growth of pathogenic microorganisms. Saccharomyces boulrdii, Lactobacillus GG, and Lactobacillus acidophilus have been shown to decrease the duration of infectious and antibiotic-induced diarrhea in adults and children.  constipation ► Physicians often use stool frequency to define constipation (most commonly fewer than three bowel movements per week); however, the “normal” frequency of bowel movement is not well established (and can vary from person to person). ► Patients more often describe constipation in terms of symptoms or a combination of quantitative and qualitative descriptors that are difficult to quanitfy: ► bowel movement frequency, ► stool size or consistency (hard or lumpy stools), ► straining upon defecation, inability to defecate at will, and symptoms such as sensation of incomplete evacuation.  Diagnostic Criteria for Functional Constipationa a Criteria fulfilled for the last 3 months with symptoms onset at least 6 months prior to diagnosis 1. Must include two or more of the following: a. Straining during at least 25% of defecations b. Lumpy or hard stools in at least 25% of defecations c. Sensation of incomplete evacuation for at least 25% of defecations d. Sensation of anorectal obstruction/blockage for at least 25% of defecations e. Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor) f. Fewer than three defecations per week 2. Loose stools are rarely present without the use of laxatives 3. There is insufficient evidence for IBS  Possible Causes of Constipation Conditions Possible Causes Cardiac disorders Heart failure GI disorders Irritable bowel syndrome Pregnancy Depressed gut motility Diverticulitis Increased fluid absorption Upper GI tract diseases from colon Anal and rectal diseases Use of iron salts Hemorrhoids Anal fissures Lifestyle factors Dietary changes Ulcerative proctitis Inadequate fluid intake Tumors Low dietary fiber Hernia Volvulus of the bowel Decreased physical activity Syphilis Neurogenic causes CNS diseases Tuberculosis Trauma to the brain Helminthic infections (particularly the medulla) Lymphogranuloma venereum Hirschsprung's disease Spinal cord injury Metabolic and endocrine Diabetes mellitus with CNS tumors disorders neuropathy Cerebrovascular accidents Hypothyroidism Panhypopituitarism Parkinson disease Pheochromocytoma Psychogenic causes Ignoring or postponing urge Hypercalcemia to defecate Enteric glucagon excess Psychiatric diseases ► Constipation may be primary or secondary. ► Primary constipation occurs without an identifiable underlying cause, whereas secondary constipation may be the result of constipating drugs, lifestyle factors, or medical disorders. ► Three primary constipation subtypes exist–normal transit, slow transit, and disordered defecation (also referred to by various other names such as pelvic floor dysfunction, anorectal dyssynergia, outlet constipation, dyscoordinated pelvic muscle activity).  Drugs Causing Constipation Analgesics Inhibitors of prostaglandin synthesis Opiates Anticholinergics Antihistamines Antiparkinsonian agents (e.g., benztropine or trihexyphenidyl) Phenothiazines Tricyclic antidepressants Antacids containing calcium carbonate or aluminum hydroxide Barium sulfate Calcium channel blockers Clonidine Diuretics (non-potassium-sparing) Ganglionic blockers Iron preparations Muscle blockers (d-tubocurarine, succinylcholine) Nonsteroidal antiinflammatory agents Polystyrene sodium sulfonate  Alarm Signs and Symptoms in Patients with Constipation 1.Hematochezia 2.Melena 3.Family history of colon cancer 4.Family history of inflammatory bowel disease 5.Anemia 6.Weight loss 7.Anorexia 8.Nausea and vomiting 9.Severe, persistent constipation that is refractory to treatment 0.New onset or worsening of constipation in elderly patients without evidence of a possible primary cause  Nonpharmacologic Therapy ► Dietary Modification and Bulk-Forming Agents ► The most important aspect of therapy for constipation for the majority of patients is dietary modification to increase the amount of fiber consumed. ► Fiber, the portion of vegetable matter not digested in the human GI tract, increases stool bulk, retention of stool water, and rate of transit of stool through the intestine. ► The three general classes of laxatives are discussed in this section: ► (a) those causing softening of feces in 1 to 3 days (bulk-forming laxatives, docusates, the poorly absorbable sugars (lactulose and sorbitol), and low-dose PEG; ► (b) those that result in soft or semifluid stool in 6 to 12 hours (diphenylmethane derivatives and anthraquinone derivatives; “stimulant-type” laxatives); and ► (c) those causing water evacuation in 1 to 6 hours (saline cathartics, castor oil, and high-dose polyethylene glycol-electrolyte lavage solution).  Gastroesophageal reflux disease (GERD) ► Gastroesophageal reflux disease (GERD) is a common medical disorder. ► A consensus definition of GERD states it is “a condition that occurs when the refluxed stomach contents lead to troublesome symptoms and/or complications. ► Esophageal GERD syndromes are classified as either symptom-based or tissue injury based: ► Symptom-based esophageal GERD syndromes may exist with or without esophageal injury and most commonly present as heartburn, regurgitation or dysphagia. ► Less commonly, odynophagia (painful swallowing) or hypersalivation may occur. ► Tissue injury–based syndromes may exist with or without symptoms. ► The spectrum of injury includes: ❖ esophagitis (inflammation of the lining of the esophagus), ❖ Barrett esophagus (when tissue lining the esophagus is replaced by tissue similar to the lining of the intestine), ❖ strictures, and esophageal adenocarcinoma. ► The key factor in the development of GERD is the abnormal reflux of gastric contents from the stomach into the esophagus. ► In some cases, gastroesophageal reflux is associated with defective lower esophageal sphincter (LES) pressure or function. ► Patients may have decreased gastroesophageal sphincter pressures related to ► (a) spontaneous transient LES relaxations, ► (b) transient increases in intraabdominal pressure, or ► (c) an atonic LES, all of which may lead to the development of gastroesophageal reflux. ► Problems with other normal mucosal defense mechanisms, such as ► abnormal esophageal anatomy, ► improper esophageal clearance of gastric fluids, ► reduced mucosal resistance to acid, ► delayed or ineffective gastric emptying, ► reduced salivary buffering of acid, ► may also contribute to the development of GERD.  Foods and Medications that May Worsen GERD Symptoms Decreased lower-esophageal sphincter pressure Foods Medications Fatty meal Anticholinergics Carminatives (peppermint, spearmint) Barbituates Chocolate Caffeine Coffee, cola, tea Dihydropyridine calcium channel blockers Garlic Dopamine Onions Estrogen Chili peppers Ethanol Nicotine Nitrates Progesterone Tetracycline Theophylline Direct irritants to the esophageal mucosa Foods Medications Spicy foods Alendronate Orange juice Aspirin Tomato juice Nonsteroidal antiinflammatory drugs Coffee Iron Quinidine Potassium chloride  Nonpharmacologic Treatment of GERD with Lifestyle Modifications Recommended lifestyle modifications for all GERD patients Elevate the head of the bed (increases esophageal clearance). Use 6- to 8-inch blocks under the head of the bed. Sleep on a foam wedge. Weight reduction (reduces symptoms) in obese patients Recommended lifestyle modifications that should be individualized to specific patients Avoid foods that may decrease lower esophageal sphincter pressure (fats, chocolate, alcohol, peppermint, and spearmint) Include protein-rich meals in diet (augments lower esophageal sphincter pressure) Avoid foods that have a direct irritant effect on the esophageal mucosa. (spicy foods, orange juice, tomato juice, and coffee) Behaviors that may reduce esophageal acid exposure Eat small meals and avoid eating immediately prior to sleeping (within 3 hours if possible; Decreases gastric volume) Stop smoking (decreases spontaneous esophageal sphincter relaxation) Avoid alcohol (increases amplitude of the lower esophageal sphincter, peristaltic waves, and frequency of contraction) Avoid tight-fitting clothes Take drugs that have a direct irritant effect on the esophageal mucosa with plenty of liquid if they cannot be avoided (bisphosphonates, tetracyclines, quinidine, and potassium chloride, iron salts, aspirin, nonsteroidal antiinflammatory drugs) Treatment ► The treatment of GERD is categorized into one of the following modalities: ► (1) lifestyle modifications and patient-directed therapy with antacids, nonprescription H2-receptor antagonists, and/or nonprescription proton pump inhibitors; ► (2) pharmacologic intervention with prescription-strength acid-suppression therapy; ► (3) and antireflux surgery  Gastritis Gastritis includes a myriad of disorders that involve inflammatory changes in the gastric mucosa, including: 1. erosive gastritis caused by a noxious irritant 2. reflux gastritis from exposure to bile and pancreatic fluids 3. hemorrhagic gastritis 4. infectious gastritis 5. gastric mucosal atrophy  Acute gastritis ► an acute mucosal inflammatory process, usually of a transient nature ► severe erosive form is an important cause of acute gastrointestinal bleeding 40  Acute gastritis ► Acute gastritis ► Acute hemorrhagic gastritis ► Acute erosive gastritis ► Acute stress gastritis 41  Causes ▪ H pylori (most common cause of ulceration) ▪ NSAIDs, aspirin ▪ Gastrinoma (Zollinger-Ellison syndrome) ▪ Severe stress (eg, trauma, burns), Curling ulcers ▪ Alcohol ▪ Bile reflux ▪ Pancreatic enzyme reflux ▪ Radiation ▪ Staphylococcus aureus exotoxin ▪ Bacterial or viral infection 42  Pathophysiology ► Erosive gastritis usually is associated with serious illness or with various drugs. Stress, ethanol, bile, and nonsteroidal anti-inflammatory drugs (NSAIDs) disrupt the gastric mucosal barrier, making it vulnerable to normal gastric secretions. ► NSAIDs and aspirin also interfere with the protective mucus layer by inhibiting mucosal cyclooxygenase activity, reducing levels of mucosal prostaglandins 43 Patients typically present with abdominal pain that has the following characteristics: □ Epigastric to left upper quadrant □ Frequently described as burning □ May radiate to the back □ Usually occurs 1-5 hours after meals □ May be relieved by food, antacids (duodenal), or vomiting (gastric) □ Typically follows a daily pattern specific to patient  Patients should be warned of known or potentially injurious drugs and agents. Some examples are as follows: NSAIDs Aspirin Alcohol Caffeine (eg, coffee, tea, colas) 45 Chronic gastritis ► Type A [fundal] gastritis ► Type B [antral] gastritis [a] hypersecretory gastritis [b] environmental gastritis. ► 46 Hypertrophic gastritis  Type A [fundal] gastritis ► circulating antibodies to parietal cells and intrinsic factor ► hypo- or achlorhydria ► a high intragastric pH and hypergastrinemia ► 10% of patients go on develop overt pernicious anemia ► associated with autoimmune disorders such as Hashimoto’s thyroiditis and Adison’s disease  Type B [antral] gastritis ► the hypersecretory type - restricted to the antrum - gastric hypersecretion - frequently symptomatic ► the environmental gastritis - the most common form of gastritis in all age groups - irregularly focal involvment of the antral mucosa - gradually extends deeper into the mucosa and cause mucosal atrophy Hypertrophic gastritis Three variants are recognized ► Menetrier’s disease ► Hypersecretory gastropathy ► Gastric gland hyperplasia [the Zollinger-Ellison syndrome] 50 ► Characterized by Giant enlargement of the gastric rugal folds ► Caused by hyperplasia of epithelial cells ( not due to inflammation ) ► ↑risk of cancer ► Includes 3 variants ► A) Menetrier’s disease ► Hyperplasia of surface mucous cells ► glandular atrophy ► excessive loss of proteins in gastric secretion (protein-losing Gastropathy) ► B) Hypersecretory Gastropathy ► Hyperplasia of parietal and chief cells ► Secondary to excessive gastrin stimulation. ► C) Zollinger - Ellison Syndrome ► Caused by Gastrinoma of Pancreas secreting gastrin elevated serum gastrin levels ► multiple peptic ulcerations in stomach, duodenum, jejunum ► Hypertrophic rugal folds & Parietal cell hyperplasia excess gastric acid production Peptic Ulcer ► A pathophysiologic imbalance between aggressive (gastric acid and pepsin) and protective factors (mucosal defense and repair) remain important issues in the pathophysiology of gastric and duodenal ulcers. ► Gastric acid is secreted by the parietal cells, which contain receptors for histamine, gastrin, and acetylcholine. ► Acid (as well as H. pylori infection and NSAID use) is an independent factor that contributes to the disruption of mucosal integrity. ► Pepsin is an important cofactor that plays a role in the proteolytic activity involved in ulcer formation. ► Pepsinogen, the inactive precursor of pepsin, is secreted by the chief cells located in the gastric fundus. ► Pepsin is activated by acid pH (optimal pH of 1.8 to 3.5), inactivated reversibly at pH 4, and irreversibly destroyed at pH 7. ► Mucosal defense and repair mechanisms (mucus and bicarbonate secretion, intrinsic epithelial cell defense, and mucosal blood flow) protect the gastroduodenal mucosa from noxious endogenous and exogenous substances. ► Acid-related diseases (gastritis, erosions, and peptic ulcer) of the upper gastrointestinal (GI) tract require gastric acid for their formation. ► Peptic ulcer disease (PUD) differs from gastritis and erosions in that ulcers typically extend deeper into the muscularis mucosa. ► There are three common forms of peptic ulcers: ► Helicobacter pylori (H. pylori)-positive, ► nonsteroidal antiinflammatory drug (NSAID)-induced, and ► stress ulcers  Potential Causes of Peptic Ulcer Common causes Helicobacter pylori infection Nonsteroidal antiinflammatory drugs Critical illness (stress-related mucosal damage) Uncommon causes of chronic peptic ulcer Idiopathic (non-H. pylori, non-NSAIDpeptic ulcer) Hypersecretion of gastric acid (e.g., Zollinger-Ellison syndrome) Viral infections (e.g., cytomegalovirus) Vascular insufficiency (e.g., crack cocaine associated) Radiation therapy Chemotherapy (e.g., hepatic artery infusions) Infiltrating disease (e.g., Crohn disease): Diseases and medical conditions associated with chronic peptic ulcer Cirrhosis Chronic renal failure Chronic obstructive pulmonary disease Cardiovascular disease Organ transplantation  H. pylori ► H. pylori is a spiral-shaped, pH-sensitive, gram-negative, microaerophilic bacterium that resides between the mucus layer and surface epithelial cells in the stomach. ► H. pylori binds to specific regions within the stomach. ► H. pylori produces large amounts of urease, which hydrolyzes urea in the gastric juice and converts it to ammonia and carbon dioxide.2 The local buffering effect of ammonia creates a neutral microenvironment within and surrounding the bacterium, which protects it from the lethal effect of gastric acid. ► Mucosal injury is produced by ► (1) elaborating bacterial enzymes (urease, lipases, and proteases), ► (2) adherence, and ► (3) H. pylori virulence factors. Legend: The natural history of Helicobacter pylori infection in the pathogenesis of gastric ulcer and duodenal ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. Date of download: 12/2/2014 Nonsteroidal Antiinflammatory Drugs ► NSAIDs, including aspirin, cause gastric mucosal damage by two important mechanisms: ► (1) direct or topical irritation of the gastric epithelium and ► (2) systemic inhibition of endogenous mucosal prostaglandin synthesis. ► Although the initial injury is initiated topically by the acidic properties of many of the NSAIDs, systemic inhibition of the protective prostaglandins limits the ability of the mucosa to defend itself against injury and thus plays the predominant role in the development of gastric ulcer. ► Cyclooxygenase (COX) is the rate-limiting enzyme in the conversion of arachidonic acid to prostaglandins and is inhibited by NSAIDs ► Two similar COX isoforms have been identified: ► cyclooxygenase-1 (COX-1) is found in most body tissue, including the stomach, kidney, intestine, and platelets; ► cyclooxygenase-2 (COX-2) is undetectable in most tissues under normal physiologic conditions, but its expression can be induced during acute inflammation and arthritis Legend: Tissue distribution and actions of cyclooxygenase (COX) isoenzymes. Nonselective nonsteroidal antiinflammatory drugs (NSAIDs) including aspirin (ASA) inhibit COX-1 and COX-2 to varying degrees; COX-2 inhibitors inhibit only COX-2. Broken arrow indicates inhibitory effects. ► Two similar COX isoforms have been identified: ► cyclooxygenase-1 (COX-1) is found in most body tissue, including the stomach, kidney, intestine, and platelets; ► cyclooxygenase-2 (COX-2) is undetectable in most tissues under normal physiologic conditions, but its expression can be induced during acute inflammation and arthritis. ► COX-1 produces protective prostaglandins that regulate physiologic processes such as GI mucosal integrity, platelet homeostasis, and renal function. ► COX-2 is induced (unregulated) by inflammatory stimuli such as cytokines and produces prostaglandins involved with inflammation, fever, and pain. ► Adverse effects (e.g., GI or renal toxicity) of NSAIDs are primarily associated with the inhibition of COX-1, whereas antiinflammatory actions result primarily from NSAID inhibition of COX-2. ► Nonselective NSAIDs, including aspirin, inhibit both COX-1 and COX-2 to varying degrees and are associated with an increased propensity to cause gastric ulcers ► In contrast, the selective COX-2 inhibitors are associated with a reduction in ulcers and related GI complications, but the benefit of celecoxib, is less that that of rofecoxib and valdecoxib. ► Aspirin and nonaspirin NSAIDs irreversibly inhibit platelet COX-1, resulting in decreased platelet aggregation and prolonged bleeding times, thereby increasing the potential for upper and lower GI bleeding.  Clinical Presentation of Peptic Ulcer Disease General Mild epigastric pain or acute life-threatening upper gastrointestinal complications Symptoms Abdominal pain that is often epigastric and described as burning but may present as vague discomfort, abdominal fullness, or cramping A typical nocturnal pain that awakens the patient from sleep (especially between 12 am and 3 am) The severity of ulcer pain varies from patient to patient and may be seasonal, occurring more frequently in the spring or fall; episodes of discomfort usually occur in clusters, lasting up to a few weeks and followed by a pain-free period or remission lasting from weeks to years Changes in the character of the pain may suggest the presence of complications Heartburn, belching, and bloating often accompany the pain Nausea, vomiting, and anorexia are more common for patients with gastric ulcer than with duodenal ulcer but may also be signs of an ulcer-related complication Signs Weight loss associated with nausea, vomiting, and anorexia Complications including ulcer bleeding, perforation, penetration, or obstruction Laboratory tests Gastric acid secretory studies The hematocrit and hemoglobin are low with bleeding, and stool hemoccult tests are positive. Tests for Helicobacter pylori Diagnostic tests Fiberoptic upper Upper gastrointestinal radiography with barium Each Secretagogue Binds to its Own Receptor and Interacts with the Others CCK2 Gastrin Ca +2 dep. pat hwa y H2 cAMP dep. pathway Histamine PP H+ Gastric M3 ay. p athw Lumen Acetylcholine +2 dep Ca Strategies for Protecting the Gastric Mucosa from Acid Exposure Mechanisms Example Cimetidine Inhibit Omeprazole H+ secretion Prostaglandins Muscarinic antagonists Prevent H+ Sucralfate contact + Neutralize Antacids H acid ► treatment Competitive H receptor Antagonist; (Cimetidine, Ranitidine, Famotidine) 2 ► Markedly inhibits basal acid secretion including nocturnal secretion. ► Proton Pump Inhibitors ► The PPIs (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, and pantoprazole) dose-dependently inhibit basal and stimulated gastric acid secretion. ► Nonselective NSAIDs should be discontinued (when possible) upon confirmation of an active ulcer. If the NSAID is stopped, most uncomplicated ulcers heal with standard regimens of an H2RA, PPI, or sucralfate.  Drug Regimens Used to Eradicate Helicobacter Pylori H2RA, H2-receptor antagonist; PPI, proton pump inhibitor. Drug #1 Drug #2 Drug #3 Drug #4 Proton pump inhibitor–based triple therapy PPI once or twice dailyb Clarithromycin 500 mg twice Amoxicillin 1 g twice daily daily or metronidazole 500 mg twice daily Bismuth-based quadruple therapy PPI or H2RA once or twice Bismuth subsalicylate 525 mg 4 Metronidazole 250–500 mg 4 Tetracycline 500 mg 4 times dailyb,c times daily times daily daily Sequential therapy PPI once or twice daily on days Amoxicillin 1 g twice daily on Metronidazole 250–500 mg twice Clarithromycin 250–500 mg 1–10b days 1–5 daily on days 6–10 twice daily on days 6–10 Second-line (salvage) therapy for persistent infections PPI or H2RA once or twice Bismuth subsalicylate 525 mg 4 Metronidazole 250–500 mg 4 Tetracycline 500 mg 4 times dailyb,c times daily times daily daily PPI once or twice daily Amoxicillin 1 g twice daily Levofloxacin 250 mg twice daily  Oral Drug Regimens Used to Heal Peptic Ulcers and Maintain Ulcer Healing Duodenal or Gastric Ulcer Maintenance of Ulcer Healing Generic Name Prescription Brand Name Healing (mg/dose) (mg/dose) Proton pump inhibitors Omeprazole Prilosec, various 20–40 daily 20–40 daily Omeprazole sodium Zegerid 20–40 daily 20–40 daily bicarbonate Lansoprazole Prevacid, various 15–30 daily 15–30 daily Rabeprazole Aciphex 20 daily 20 daily Pantoprazole Pantoprazole, various 40 daily 40 daily Esomeprazole Nexium 20–40 daily 20–40 daily Dexlansoprazole Dexilant 30–60 daily 30 daily H2-receptor antagonists Cimetidine Tagamet, various 300 four times daily 400–800 at bedtime 400 twice daily 800 at bedtime Famotidine Pepcid, various 20 twice daily 20–40 at bedtime 40 at bedtime Nizatidine Axid, various 150 twice daily 150–300 at bedtime 300 at bedtime Ranitidine Zantac, various 150 twice daily 150–300 at bedtime 300 at bedtime Promote mucosal defense Sucralfate Carafate, various 1 g 4 times daily 1–2 g twice daily 2 g twice daily 1 g 4 times daily Antacids ► Antacids are weak bases that neutralize HCl in the stomach; ► They do not decrease the secretion of acid, and in some cases increase secretion; ► They do not suppress nocturnal acid secretion 1. Neutralize acid 2. Decrease acid load to duodenum 3. Diminish pepsin activity Drugs for Acid-Peptic Disorders - Antacids ► Magnesium hydroxide ► Magnesium trisilicate ► Magnesium-aluminum mixtures ► Calcium carbonate ► Sodium bicarbonate  Inflammatory Bowel Diseases: Ulcerative Colitis, Crohn Disease The exact cause of inflammatory bowel disease (IBD) is unknown, although there are components that appear to be infectious and other components that suggest immune dysregulation.  Comparison of the Clinical and Pathologic Features of Crohn's Disease and Ulcerative Colitis Feature Crohn's Disease Ulcerative Colitis Clinical Malaise, fever Common Uncommon Rectal bleeding Common Common Abdominal tenderness Common May be present Abdominal mass Common Absent Abdominal pain Common Unusual Abdominal wall and internal fistulas Common Absent Distribution Discontinuous Continuous Aphthous or linear ulcers Common Rare Pathologic Rectal involvement Rare Common Ileal involvement Very common Rare Strictures Common Rare Fistulas Common Rare Transmural involvement Common Rare Crypt abscesses Rare Very common Granulomas Common Rare Linear clefts Common Rare Cobblestone appearance Common Absent  Ulcerative Colitis (UC) ► UC is confined to the rectum and colon and affects the mucosa and the submucosa. ► The primary lesion of UC occurs in the crypts of the mucosa (crypts of Lieberkuhn) in the form of a crypt abscess. Here, frank necrosis of the epithelium occurs. ► The typical ulceration patterns include a collar-button ulcer, and pseudopolyps. ► The extensive mucosal damage seen in UC can result in significant diarrhea and bleeding, although a small percentage of patients experience constipation. ► A major complication is toxic megacolon, which is a segmental or total colonic distension of greater than 6 cm with acute colitis and signs of systemic toxicity. ► Other complications include hemorrhoids, anal fissures, or perirectal abscesses and are more likely to be present during active colitis. ► The risk of colonic carcinoma is much greater for patients with UC as compared with the general population and begins to increase 10 to 15 years after the diagnosis of UC. ► Hepatic complications include fatty liver, pericholangitis, chronic active hepatitis, and cirrhosis. ► Arthritis commonly occurs in IBD patients and is typically asymmetric (unlike rheumatoid arthritis) and migratory, involving one or a few usually large joints such as knees, hips, ankles, wrists, and elbows. ► Ocular complications including iritis, uveitis, episcleritis, and conjunctivitis occur in up to 10% of patients with IBD. ► Skin and mucosal lesions associated with IBD include erythema nodosum, pyoderma gangrenosum, and aphthous ulceration. Crohn's Disease ► Crohn's disease is best characterized as a transmural inflammatory process. ► The terminal ileum is the most common site of the disorder, but it may occur in any part of the GI tract from mouth to anus. ► Regardless of the site, bowel wall injury is extensive and the intestinal lumen is often narrowed. ► The mesentery first becomes thickened, edematous, and then fibrotic. ► Ulcers tend to be deep and elongated and extend along the longitudinal axis of the bowel, at least into the submucosa. ► The “cobblestone” appearance of the bowel wall results from deep mucosal ulceration intermingled with nodular submucosal thickening. ► Small bowel stricture and subsequent obstruction is a complication that may require surgery. ► Fistula formation is common and occurs much more frequently than with UC. ► Systemic complications of CD are common, and similar to those found with UC. Arthritis, iritis, skin lesions, and liver disease often accompany CD treatment ► The first line of treatment for mild to moderate UC or Crohn's colitis consists of oral aminosalicylates, such as sulfasalazine ormesalamine; mesalamine or steroid enemas or suppositories may be used for distal disease. ► Corticosteroids are often required for acute UC or CD. ► Infliximab is a treatment option for patients with moderate to severe active UC and for those patients with UC who are dependent on corticosteroids. ► Azathioprine or mercaptopurine may be used for maintenance of remission.