GI Drugs PDF

8 GASTRIC ACID SECRETION Mechanism of gastric acid secretion Gastric parietal cells contain carbonic anhydrase, which is an enzyme that transforms CO2 and H2O into H+ and HCO−3. HCO−3 is transported out of the parietal cell into the bloodstream via a Cl −/HCO− exchange. 3...

8 GASTRIC ACID SECRETION Mechanism of gastric acid secretion Gastric parietal cells contain carbonic anhydrase, which is an enzyme that transforms CO2 and H2O into H+ and HCO−3. HCO−3 is transported out of the parietal cell into the bloodstream via a Cl −/HCO− exchange. 3 H is pumped out of the parietal cell via an H+/K+ ATPase, and Cl− follows + H+ out of the parietal cell into the stomach lumen. Regulation of gastric acid secretion Stimulation of acid secretion  Gastrin stimulates H+ secretion by interacting with an uncharacterized receptor on the parietal cell. Histamine activates H2 receptors on the parietal cell, leading to an increase in cyclic AMP levels, which acts to stimulate acid secretion. The vagus nerve stimulates acid secretion through two pathways— through activation of an M3 receptor on the parietal cell and through the activation of an M3 receptor on the G cell of the stomach, which is responsible for secreting gastrin. Inhibition of acid secretion Chyme directly inhibits acid secretion. Low pH in the stomach inhibits gastrin secretion, thereby leading to a decrease in acid secretion. A 34-year-old woman presents to your primary care clinic complaining of heartburn. She tells you that the pain begins after spicy meals and is generally worse when she lies down to go to sleep. She denies dysphagia, weight loss, low-grade fevers, or blood in the stool. Physical examination is unremarkable. You tell her that she likely has gastroesophageal reflux disease and you explain to her that there are several pharmacologic treatment options, including an over- the-counter class of drugs that act as weak bases to reduce the acidity in the stomach. Antacids Similar Aluminum hydroxide; magnesium hydroxide; calcium Drugs carbonate; sodium bicarbonate. Mechanism Antacids are weak bases that form a salt and water upon of Action reaction with gastric hydrochloric acid. The net result is to increase the pH and thereby reduce the acidity of the gastric contents. Furthermore, since pepsin is inactivated at pH levels >4, antacids may also act to decrease the peptic activity of protein breakdown. Also, it has been postulated that antacids may increase the mucosal barrier of the gastric lining by stimulating prostaglandin synthesis.  Clinical Treatment of gastroesophageal reflux disease; also used to Uses promote the healing of duodenal ulcers. Side Aluminum hydroxide: Constipation. Effects Magnesium hydroxide: Diarrhea. Calcium carbonate: Hypercalcemia; milk-alkali syndrome. Sodium bicarbonate: Flatulence; metabolic alkalosis. Other A 40-year-old woman presents to your clinic with a complaint of black-colored stools and epigastric pain. You refer her for endoscopy, which reveals evidence of peptic ulcer disease. Biopsy results do not reveal the presence of Helicobacter pylori infection. In addition to starting her on a proton pump inhibitor, you decide to prescribe a medication, which acts to enhance the mucosal barrier in the stomach through the promotion of prostaglandin synthesis. Mucosal Protective Agents Similar Drugs Mechanism Sucralfate: believed to enhance the mucosal barrier either of Action through the stimulation of prostaglandin synthesis or by acting as a physical barrier itself and thereby protecting the delicate mucosal lining from the acidic stomach contents. Bismuth subsalicylate: believed to inhibit intestinal motility through inhibition of prostaglandin synthesis, to bind intestinal toxins produced by Escherichia coli, and to stimulate fluid absorption from the bowel lumen. Clinical These drugs are used in the treatment of peptic ulcer disease Uses and to promote the healing of duodenal ulcers. Bismuth subsalicylate, specifically, is also used as an anti-diarrheal agent as well as part of quadruple therapy to treat H. pylori.  Side Sucralfate: constipation. Effects Bismuth subsalicylate: dark-colored tongue and stool; hinders tetracycline absorption. Other Since sucralfate requires an acidic environment for activation, it should not be taken with antacids, H2 blockers, or proton pump inhibitors. Furthermore, because sucralfate binds non- specifically to positively charged molecules in the lumen, it can interfere with the absorption of other drugs if they are taken simultaneously. As a result, other drugs must be taken at least 2 hours before sucralfate administration. A 62-year-old man presents to your primary care office for a follow-up visit regarding his multiple medical problems, including gout and atrial fibrillation, for which he is anti-coagulated with warfarin. He tells you that he has been feeling generally well, although he has been suffering from some heartburn over the past couple of months. On physical examination, you notice the appearance of some mild gynecomastia. Furthermore, laboratory testing reveals that his PT is much higher than would be expected given his current dose of warfarin. On further questioning, he admits that he has been taking a drug that his wife was prescribed for her gastroesophageal reflux disease many years ago. You advise him to stop taking his wife’s medication immediately, as it is likely causing both his gynecomastia as well as his elevated PT levels. H2 Receptor Blockers Similar The H2 receptor blockers include ranitidine, cimetidine, Drugs famotidine, and nizatidine. Mechanism This class of drugs acts by reversibly blocking the binding of of Action histamine to the H2 receptor that is present on the parietal cells of the gastric mucosa. By inhibiting stimulation of the H2 receptor, cyclic AMP levels are decreased, which then leads to the decreased activity of the H+/K+ proton pump. The end  result is that gastric acid secretion is decreased. Clinical Treatment of gastroesophageal reflux disease, peptic ulcer Uses disease, and other diseases associated with gastric ulcers. Side Headache; Cimetidine, in particular, has been shown to have Effects anti-androgenic effects, leading to gynecomastia, and is also a known CYP450 inhibitor (and, therefore, can cause decreased hepatic metabolism of certain drugs, such as warfarin, anti- epileptics, and oral contraceptives). Other A 59-year-old man presents to the clinic complaining of upper abdominal pain after meals. Upon further questioning, he tells you that he has lost 15 lb over the last 2 months because of a decreased appetite connected with the pain associated with his meals. He denies any frank blood in his stools, but he has noticed that his stool has been darker recently. His social history is significant for heavy alcohol and tobacco use over the past 35 years. You refer him to a gastroenterologist for an endoscopic evaluation of his stomach as you suspect that he may have gastric ulcers. For symptomatic relief, in the meantime, you place him on a drug that will directly suppress gastric acid secretion by inhibiting the H+/K+ ATPase pump in the gastric lining. Proton Pump Inhibitors Similar The proton pump inhibitors include omeprazole, lansoprazole, Drugs pantoprazole, esomeprazole, rabeprazole, and dexlansoprazole. Mechanism This class of drugs binds directly to and irreversibly inhibits of Action the H+/K+ ATPase pump, which is present on the parietal cells of the gastric mucosa, thereby suppressing gastric acid secretion. Clinical Treatment of peptic ulcer disease, gastroesophageal reflux Uses disease, Zollinger-Ellison syndrome, and esophagitis. Also used  as part of regimen to treat H. pylori infection. Side Headache; rash; possible increased risk for fractures in the Effects elderly; long-term use may cause atrophic gastritis as well as deficiencies of vitamins that require acid for absorption (e.g., calcium, iron, magnesium, vitamin B12). Other Animal studies have shown an increased incidence of gastric carcinoid tumors with prolonged administration of omeprazole; however, there have been no reports of this in humans. A 68-year-old woman with ovarian cancer is admitted to the hospital for a course of chemotherapy. After she has received her first treatment, she begins to complain of severe nausea and she vomits twice. To treat her nausea and vomiting, she was initially given an anti-emetic medication; however, you are notified that her blood pressure dropped to 90/50 mm Hg soon after administration of this medication. You decide to switch her anti-emetic medication to a drug that acts by blocking 5-HT3 receptors. Ondansetron Similar Drugs Mechanism Ondansetron acts to block 5-HT3 receptors. 5-HT3 receptors of Action are present in the chemoreceptor trigger zone in the brainstem, which is part of the vomiting reflex pathway, and in the gastrointestinal tract. When the 5-HT3 receptors are activated in the GI tract by the release of serotonin from damaged enterochromaffin cells, a signal is sent via the vagus nerve to the brainstem to activate the vomiting reflex pathway. By blocking 5-HT3 receptors, ondansetron inhibits activation of the vomiting reflex pathway. Clinical Treatment of nausea and vomiting.  Uses Side Headache; constipation. Effects Other H1 receptor antagonists (e.g., diphenhydramine, dimenhydrinate, promethazine, and doxylamine) are also used to treat nausea and vomiting. H1 receptors are present throughout the body, including in the GI tract. By blocking these receptors in the GI tract, GI tract motility is decreased, and symptoms of nausea and vomiting are lessened. Side effects of this class of drugs include blurry vision and dry mouth. Other drugs used to treat nausea and vomiting associated with chemotherapy include haloperidol, benzodiazepines, corticosteroids, and marijuana derivatives. You are seeing a 53-year-old insulin-dependent diabetic patient, who is 3 days post-cholecystectomy on your surgical service. His bowel exam is normal with no signs of bowel obstruction and his surgical site is healing well. Nevertheless, he has had significant nausea and vomiting since his surgery and he complains of some mild abdominal bloating. You suspect that he may be experiencing some mild gastroparesis, likely related to both his postsurgical state as well as his diabetes. You decide to administer a medication that acts at the D2 dopamine receptors in the chemoreceptor trigger area and will both stimulate his gastric motility as well as treat his nausea and vomiting. Metoclopramide Similar Drugs Mechanism Metoclopramide acts as an antagonist at the D2 dopamine of Action receptors in the chemoreceptor trigger zone of the medulla by raising the threshold of chemoreceptor activity required and,  thereby, blocking activation of the vomiting reflex pathway. Metoclopramide has also been shown to stimulate gastric and small intestinal motility. Although the exact mechanism of action of this effect is unclear, this drug does have cholinomimetic activity which can lead to increased activation of the myenteric plexus of the enteric nervous system. Clinical Used to treat diabetic gastroparesis. Uses Also used as a potent anti-emetic agent. Side Sedation; hypotension; diarrhea; extrapyramidal symptoms, Effects including tardive dyskinesia; peripheral edema; depression; neuroleptic malignant syndrome Other Prochlorperazine is another anti-emetic agent, which acts by blocking the D2 dopamine receptor in the chemoreceptor trigger zone, thereby blocking activation of the vomiting reflex pathway. There is also evidence that prochlorperazine may have some antagonistic activity at anti-cholinergic receptors as well as α1 adrenergic receptors. Similar to metoclopramide, side effects include hypotension and extrapyramidal symptoms, including tardive dyskinesia. An 82-year-old woman presents to your primary care clinic complaining of constipation. While taking a thorough history, you discover that she had been experiencing some right shoulder pain, for which she has been taking her late husband’s leftover OxyContin for the last 2 months. You advise her that it is not a good idea to take other people’s medications and you instruct her to discontinue using the OxyContin. In addition to working up the cause of her right shoulder pain, you prescribe her a new pain regimen as well as two medications that will treat her constipation by softening her stool and by increasing gut motility by mucosal stimulation. Laxatives Similar Irritants or stimulants: Castor oil, senna, bisacodyl.  Drugs Bulking laxatives: Lactulose, sorbitol, polyethylene glycol, magnesium salts. Stool softeners: Docusate, mineral oil. Mechanism Irritants or stimulants: In general, these compounds act to of Action increase intestinal peristalsis through mucosal irritation or stimulation, thereby leading to increased gut motility. Bulking laxatives: In general, these compounds draw water into the intestine via osmosis, thereby distending the bowel, which results in increased intestinal motility. Stool softeners: These compounds become emulsified with the stool, thereby softening the stool. Clinical Treatment of constipation; also used for bowel preparation for Uses colonoscopic procedures. Side Abdominal cramps; diarrhea. Effects Other Lactulose is also used in the treatment of hepatic encephalopathy. Bacteria in the intestine acts to degrade lactulose into lactic acid and acetic acid, which are two compounds that promote nitrogen excretion and hence improves the encephalopathy associated with hyperammonemia. A 54-year-old man with a history of alcoholic cirrhosis presents to the Emergency Department with altered mental status. He is jaundiced and quite lethargic, requiring aggressive and repeated verbal stimulation to rouse. When questioned, he is oriented only to person, not place or time. On physical exam, you note that his hands flap noticeably when he extends his arms and dorsiflexes his hands. Among other labs, you order an ammonia level and start the patient on a drug that will help to lower serum levels of ammonia in the hopes of treating his encephalopathy. Lactulose  Similar Drugs Mechanism Bacteria in the intestines degrade lactulose into lactic acid and of Action acetic acid, which are two compounds that acidify the gut pH and promote nitrogen excretion, thereby improving the encephalopathy associated with hyperammonemia. Lactulose is also an osmotic laxative which acts by drawing water into the intestinal lumen. Clinical Treatment of hepatic encephalopathy; also used as a laxative. Uses Side Abdominal cramps; diarrhea. Effects Other Rifaximin is a non-absorbable derivative of rifampin that inhibits bacterial RNA polymerase, thereby resulting in the reduction of ammonia-producing bacteria in the gut. It has been shown to be effective in reducing the risk of recurrence of hepatic encephalopathy. Rifaximin is also used to treat diarrhea associated with irritable bowel syndrome and foreign travel. Side effects include peripheral edema, fatigue, and nausea. A 23-year-old man presents to your clinic with a list of vaccines and prescription medications, which he will require for his summer international travel. He asks if there is anything else he should take with him in terms of medications. After reviewing his list, you see that he has not listed any drugs that could be used to treat simple traveler’s diarrhea. You suggest that he take a medication with him which works by binding to opioid receptors in the intestine and thereby decreasing gut peristalsis; however, you instruct him to seek medical attention if he develops a high fever or notices blood in his stool. Anti-Diarrheal Agents  Similar Anti-diarrheal agents include diphenoxylate and loperamide. Drugs Mechanism Diphenoxylate and loperamide act by binding to opioid of Action receptors in the intestine, which leads to the inhibition of acetylcholine release and thereby results in decreased gut peristalsis. Clinical Used for the symptomatic treatment of diarrhea. Uses Side Constipation; abdominal pain and bloating. Effects Other Bismuth subsalicylate is also used as an anti-diarrheal agent (see Mucosal Protective Agents card in Chapter 8). A 28-year-old man presents to the gastroenterologist’s office complaining of abdominal pain and alternating bouts of diarrhea and constipation. Your physical examination is significant for a temperature of 100º F and several oral aphthous ulcers. You decide to order an upper gastrointestinal series with a small bowel follow-through, the results of which are suggestive of mild Crohn’s disease. Since the patient is adverse to the idea of taking steroids, you decide to begin the patient on a medication that is structurally related to aspirin. Sulfasalazine Similar Other 5-ASA derivatives include olsalazine and mesalamine. Drugs Mechanism In the colon, bacteria metabolize sulfasalazine into its two of Action constituents, sulfapyridine and 5-ASA. 5-ASA acts as an anti- inflammatory by inhibiting prostaglandin and leukotriene production through the inhibition of COX. 5-ASA may also scavenge for oxygen radicals, thereby preventing further mucosal damage.  Clinical Treatment of inflammatory bowel disease; also used in the Uses treatment of rheumatoid arthritis and juvenile arthritis. Side GI upset; skin rash; headache; bone marrow suppression; Effects infertility. Other Because this drug is metabolized to sulfapyridine, which can impair folic acid absorption, this drug should be administered with folic acid supplementation. A 76-year-old woman presents to your primary care clinic complaining of right upper quadrant abdominal pain after meals. Upon further questioning, you discover that the pain tends to occur after she eats fast food or after she drinks alcohol. On physical examination, you note that she is obese and has mild tenderness in the right upper quadrant of her abdomen. An ultrasound of her gallbladder demonstrates the presence of several gallstones. Laboratory studies reveal elevated cholesterol levels. You tell the patient that you believe that she is suffering from cholesterol gallstones. She has a complicated past medical history and is not a good surgical candidate for a cholecystectomy. You decide to place her on a lipid-lowering regimen as well as on a drug that is specifically aimed at dissolving cholesterol gallstones. Ursodiol Similar Chenodiol. Drugs Mechanism Ursodiol decreases the incidence of cholesterol gallstones in of Action three ways: (1) It inhibits HMG-CoA reductase, thereby decreasing cholesterol synthesis; (2) It decreases intestinal reabsorption of cholesterol; and (3) It inhibits the secretion of cholesterol into bile. Clinical Treatment of primary biliary cirrhosis; also used to treat Uses cholesterol gallstones in patients who desire an alternative to cholecystectomy. Side GI upset. Effects Other