Pharmacology Chapter 33 THERAPY OF GI DISORDERS: PEPTIC ULCERS, GERD, AND VOMITING.

Hypermotility

increase in muscle tone or contractions causing faster clearance of substances through the GI tract.

Dyspepsia

indigestion

Digestion

mechanical and chemical breakdown of foods into smaller units.

Ulcer

open sore in the mucous membranes or mucosal linings of the body

Perforation

opening in a hallow organ, such as a break in the intestinal wall

Chyme

partially digested food and gastric secretions that move into the duodenum from the stomach by peristalsis.

Hepatic microsomal metabolism

specific enzymes in the liver (P-450 family) that metabolize some drugs and can be increased (stimulated) by some medications or decreased (inhaled) by other medications so that therapeutic drug blood levels are altered.

Abortifacient

substance that induces abortion

Antisecretory

substance that inhibits secretion of digestive enzymes, hormones, or acid.

Absorption

the uptake of nutrients from the gastrointestinal (GI) tract.

Emesis

vomiting

MANAGEMENT OF GASTROINTESTINAL DISORDERS

-treatment of peptic ulcers is directed toward the source of the irritation and pain and allowing the mucosal sores to heal. ANTIBIOTIC THERAPY FOR H. pylori -requires antibiotic therapy to eradicate the bacteria. -antibiotic monotherapy is not recommnended because bacterial resistance develops. -the antibiotics of choice include amoxicillin, tetracycline, metronidazole (flagyl), and clarithromycin (Biaxin) because H. pylori is sensitive to them. -Triple therapy = two antibiotics plus bismuth -quadruple therapy= triple combination plus a proton pump inhibitor (PPI). ANTIULCER DRUG THERAPY -without antibiotics is used in the management of peptic ulcers and GERD where H.pylori is not the causative agent. Two primary mechanisms are involved in drug-mediated ulcer healing: 1. reduction of gastric acidity and 2. enhancement of mucosal barrier defenses. ANTISECRETORY DRUGS include H2-receptor antagonists (antihistamines), prostaglandins, and proton pump inhibitors. ANTACIDS neutralize the acid already present. SUCRALFAE (Carafate) is neither an antacid nor an antisecretory drug. It acts to enhance the mucosal defense by a local action at the site of the ulcer. -recurrent ulcers require surgical repair to avoid further damage, pain, and hemorrhage.

PEPTIC ULCER AND GERD

CAUSES OF GERD -in GERD, the LES relaxes inappropriately such that gastric acid washes back (reflux) into the esophagus. -when this occurs out of synchrony with peristalsis, the acid remains in contact with esophageal tissue longer. -certain foods are known to relax this sphincter (reduce lower esophageal pressure) in anticipation of digestion. -once the mucosa is eroded, HCl can directly injure the cells. GERD drug therapy: 1. Suppresses acid production, 2. Prevents erosion, and 3. Provides symptomatic relief

PROCESS OF DIGESTION

ACETYLCHOLINE (ACH), GASTRIN, AND HISTAMINE are the MAJOR STIMULATORS for the release of gastric juices. -ACH is a potent stimulator and binds to receptors on the chief, G, enterochromaffin-like (ECL), and parietal cells, stimulating the release of pepsin, gastrin, histamine, and HCL respectively. -histamine binds to receptors on the parietal cells and greatly enhances the released volume and concentration of HCL. Drugs that block histamine release and the pump that releases HCL from the parietal cells can drastically diminish the release of HCl. The secretion of Hcl causes the contents of the stomach to become extremely acidic (pH 0.8). This acid pH is necessary to activate the digestive enzymes such as pepsin. -GASTRIN acid is even produced and secreted between meals in response to appropriate stimuli. Acid secretion between meals, during the evening hours, and during sleep reduces bacterial growth in the stomach, thus minimizing the risk of infection. Normally, the cells of the GI tract are protected from the destructive action of acid and pepsin. The mucosal lining of these organs is continuously lubricated with secretions of mucus and alkaline fluid to prevent autodigestion (self-destruction). -there is also rapid replacement (turnover) of the epithelial cells to help minimize erosion. These protective mechanisms are extremely important during the evening hours, when acid is secreted into an empty stomach. Anything that interferes with the protective function of the mucosal cell barrier may contribute to the production of ulcers. -The organs of the upper GI tract are primarily concerned with digestion and absorption of nutrients -The stomach and small intestine secrete several hormones and enzymes that aid in digestion and absorption -Specialized cells in the stomach produce hydrochloric acid and proteolytic enzymes which break down food particles into an absorbable forms -Acetylcholine, gastrin, and histamine are the major stimulators for the release of gastric juices -The mucosal lining of the gi tract is lubricated with secretions of mucus and alkaline fluid that protect it from autodigestion

PROKINETIC DRUGS FOR THE MANAGEMENT OF GERD

Adverse effects and contraindications May produce cardiovascular effects such as palpitations and tachycardia Common adverse effects are fatigue, restlessness, nausea, and diarrhea Long-term or high-dose use increases the risk of tardive dyskinesia Contraindicated in patients in whom motility may precipitate Hemorrhage or perforation (bowel perforation or obstruction) Contraindicated in patients who are epileptic or area receiving drugs that are likely to cause extrapyramidal reactions

PEPTIC ULCER AND GERD

CAUSES OF PEPTIC ULCERS -PEPTIC ULCERS are open sores that develop on the mucosal lining of the stomach and duodenum, where acid and pepsin activity are greatest. -There is no simple cause of ulcers. The most common cause of peptic ulcers is an infection caused by a bacterium called Helicobacter pylori (H. pylori). -it is believed that the bacteria is acquired through contaminated water, poorly washed food, and uncooked food, although transmittal through infected saliva may also occur. -The next most common cause of peptic ulcer in the United States is long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). -NSAIDs and STEROIDS are ULCEROGENIC because they inhibit the secretion of protective mucus and interfere with the normal production of the mucosal lining. -NSAIDs block the production of certain prostaglandins that inhibit gastric secretions. -if the prostaglandins that inhibit gastric secretions are blocked, more gastric acid is produced, increasing the likelihood of developing an ulcer. -whether gastric or duodenal, peptic ulcers are associated with acid-induced injury to the mucosa. -some individuals with or without H. pylori present secrete excess amounts of gastric acid (hyperacidity or hyperchlorhydria) even when food in not present in the stomach. -other individuals may not produce enough protective mucus or inhibitory enzyme to stop acid secretion. -there is also evidence that some people are genetically susceptible to ulcer formation. -usually, a combination of ulcerogenic factors is involved in the development of peptic ulcers. (for example, alcohol, smoking, and increased cholinergic (vagus) activity stimulate the secretion of acid.

ACID NEUTRALIZATION: (ANTACIDS)

Clinical indications: 1. Hyperacidity associated with peptic ulcers 2. Upset stomach: a. Heartburn, b. GERD, and c. acid indigestion Mechanism of action: -React with HCl, forming water and salts- neutralizes acidity -Administered orally -Short duration of action

PROCESS OF DIGESTION

DIGESTIVE ENZYMES -there are three phases of gastric acid secretion involved in digestion of foods: 1. CEPHALIC (sight, smell, taste and thought of food stimulate the release of gastric juices before the bolus of food actually reaches the stomach 2. GASTRIC juices are predominately bydrochloric acid (HCL) and an enzyme, PEPSIN. During this phase, the stomach distends when food enters, again stimulating the release of gastric juices. -the parietal cells (Oxyntic cells) located in the stomach are responsible for the secretion of gastric acid (HCL). -the secretion of HCL decreases the pH, which activates digestive enzymes such as pepsin so it can partially digest proteins in the food. -the volume of partially digested foods (chyme) entering the duodenum distends it and stimulates the release of gastric juices. -The protein by-products (peptides and amino acids) within the chyme also stimulate the secretion of gastric juices. 3. INTESTINAL phrase, the presence of acid and fat inhibit their release. this action prevents excess secretion of HCL and pepsin, which could damage the GI tissue.

LIFE STYLE MODIFICATIONS

Diet and Lifestyle modifications have an important role in therapy for peptic ulcers and gerd: Stop smoking Avoid caffeine and alcohol Reduce stress Eliminate nsaids if possible Eat smaller meals Eliminate foods that trigger/worsen symptoms Lose weight (if overweight) Elevate the head of the bed

PEPTIC ULCER AND GERD

GASTROINTESTINAL ESOPHOGEAL REFLUX DISEASE (GERD) -is a disorder characterized by HEARTBURN (irritation and/or burning in the chest or throat). This symptom is part of a CHRONIC DISEASE. -in GERD, heartburn occurs after meals, worsens when the patient is lying down, and involves regurgitation of digestive juices into the esophagus. -In severe GERD, the patient also may have signs of chronic blood loss, ulcerative esophagitis and strictures , and fibrous tissue bands resulting from the chronic injury to the esophagus. -the normal barriers to regurgitation of acid involve contraction of the lower esophageal sphincter (LES), dilution of acid by swallowed saliva, peristalsis that moves digested material toward the stomach, and, ultimately, resistance by the mucosal lining.

ANTISECRETORY DRUGS:

SUPPRESSION OF GASTRIN ACID -Histamine is a potent stimulator of gastric secretions -Histamine receptors are found in the gastric mucosa -Antihistamine (H2) receptor antagonists: -Reduce interaction between histamine and H2 receptors reducing acid secretions (Includes Tagamet, Pepcid, zantac) Used to treat gastric ulcers, gerd, and for patients who must continue nsaid use Adverse effects are few, especially during short term use ---->Headache or constipation Proton Pump Inhibitors (Prilosec, Nexium, prevacid) 1. Directly inhibit the system that releases hydrochloric acid 2. Clinical indications a. With antibiotics in treatment of ulcers associated with H. pylori b. Benign gastric ulcers and GERD c. Promote healing and prevent recurrence Adverse effects: -Abdominal pain, headache, diarrhea, constipation, and nausea SPECIAL CONSIDERATIONS: -Systemic absorption: Most are nonsystemic AND Prolonged use of sodium bicarbonate may result in metabolic alkalosis. adverse effects: Chronic use may result in acid rebound: -Increased stomach pH (ALKALINE) CAUSES CELLS TO INCREASE SECRETION OF ACID -LONG-TERM USE CAN ALSO INCREASE SODIUM WHICH CAN BE SIGNIFICANT FOR PATIENTS WITH HYPERTENSION OR CONGESTIVE HEART FAILURE (WATER FOLLOWS SODIUM)

PEPTIC ULCER AND GERD

SYMPTOMS OF PEPTIC ULCER -regardless of the cause, peptic ulcers may be accompanied by periodic pain, nausea, loss of appetite, and vomiting. -the pain is characteristically described as a dull, gnawing, burning sensation, and it often resembles heartburn (a burning sensation behind the sternum). -duodenal pain is usually (but not always) relieved by food, whereas gastric pain is brought on by food. (pain may be strong enough to awaken patient from their sleep). -Chronic erosion of the mucosa may produce a peroforation in the GI wall. -symptoms of the perforation include blood in stools or vomit. The immediate danger is that the GI peraforation will lead to hemorrhage, hypotension, and shock. -Antibiotic treatment for H.pylori -Antiulcer drug therapy: 1. Reduces gastric acidity 2. Enhances mucosal barrier defenses 3. Involves the use of antisecretory drugs and antacids

PROKINETIC DRUGS FOR THE MANAGEMENT OF GERD

Special considerations Systemic absorption Most are nonsystemic Prolonged use of sodium bicarbonate may result in metabolic alkalosis adverse effects Chronic use may result in acid rebound Increased stomach pH (ALKALINE) CAUSES CELLS TO INCREASE SECRETION OF ACID LONG-TERM USE CAN ALSO INCREASE SODIUM WHICH CAN BE SIGNIFICANT FOR PATIENTS WITH HYPERTENSION OR CONGESTIVE HEART FAILURE (WATER FOLLOWS SODIUM)

Management of Emesis

Vomiting Natural defense mechanism that may Signals disease or organ dysfunction May be involuntary or self-induced Associated with many causes including flu, pregnancy, motion sickness, ear infections, and certain drugs Persistent vomiting results in electrolyte, fluid, and acid-base imbalances Commonly used antiemetics are antihistamines and phenothiazines that inhibit dopaminergic or cholinergic receptors Serotonin antagonists (Zofran) prevent serotonin from initiating cholinergic nerves Antihistamines (reglan) relieve vomiting and exhibit anticholinergic effects Adverse effects include dry mouth, sedation, drowsiness, diarrhea Phenothiazines (Promethazine), metoclopramide (reglan), and ondansetron (Zofran) have the potential of producing extrapyramidal reactions Safety during pregnancy has not been established

Prokinetic Drug

a drug that increases lower esophageal sphincter tone and stimulates motility in the upper gastrointestinal tract

heartburn (acid indigestion)

a painful burning feeling behind the sternum that occurs when stomach acid backs up into the esophagus.

Hyperacidity

abnormally high degree of acidity (for example, pH less than 1) in the stomach.

Hypophosphatemia

abnormally low concentrations of phosphate in the circulating blood.

Proteolytic

action that causes the decomposition or destruction of proteins

Ulcerogenic

capable of producing minor irritation or lesions to an integral break in the mucosal lining (ulcer).

Parietal (oxyntic) cell

cell that synthesizes and releases HCL into the stomach lumen.

Enterochromaffin-like cells (ECL)

cells that synthesize and release histamine

Antacid

drug that neutralizes hydrochloric acid (HCL) secreted by the stomach

Acid Rebound

effect in which a great volume of acid is secreted by the stomach in response to the reduced acid environment caused by antacid neutralization.

Hypercalcemia

elevated concentration of calcium ions in the circulating blood.

Pepsin

enzyme that digests protein in the stomach.

Hyperchlorhydria

excess hydrochloric acid in the stomach

GERD

gastroesophageal reflux disease