Study Questions-gi Tract

Study Questions-GI Tract Drugs 1. Describe the major pathways used to regulate acid secretion by parietal cells. The major stimulus of acid secretion of the parietal cells is regulated by the release of substances from the vagus nerve and the G-cells. The vagus nerve releases Ach which interact in two ways with the parietal cells: One mechanism is through ACh's interaction with muscarinic receptors (M3) to activate the Ca++ pathway. This interaction stimulates the H/K ATPase, bringing K+ into the cell and releasing acid (H+) into the lumen of the stomach. The other mechanism is through stimulation of the ECl cells to release histamine. Histamine interacts the the H2 receptor on the parietal cell stimulating the cAMPdependent pathway. This stimulation activates the H/K ATPase. The G-cells release gastrin which goes through the blood (endocrine pathway) to interact with CCK2 receptors. Gastrin can interact with CCK2 receptors on parietal cells stimulating the Ca++ dependent pathway, thereby stimulating the H/K ATPase. Gastrin can also interact with CCK2 receptors on ECL cells to activate histamine. Histamine interacts the the H2 receptor on the parietal cell stimulating the cAMPdependent pathway. This stimulation activates the H/K ATPase. EP3 receptors also have an effect on parietal cells acid secretion. Fatty acids stimulate the production of prostaglandins (PGE2) which interact with EP3 receptors. This interaction has an inhibitory affect on the cAMP-dependent pathway, inactivating the H/K ATPase and decreasing acid secretion. 2. How do H2 antagonists inhibit acid secretion and how are these drugs used to treat peptic ulcer disease? H2 AT are competitive inhibitors of H2 receptors which do not penetrate the blood brain barrier, can cross the placenta, are excreted into breast milk, inhibit P450 and are renally excreted. They compete with histamine at the H2 receptors, decreasing the binding of histamine, meaning there is not as much activation of the cAMP-dependent pathway. This suppression causes a decrease in gastric acid secretions. They only cause a 60-70% suppression of acid secretion but have a greater affect on nocturnal acid secretions than do PPIs. 3. Describe how omeprazole is converted to an active drug following oral administration. Along with the other PPIs, omeprazole is a prodrug that is formulated as an acid-resistant enteric-coated formulation. Once in the parietal cell canaliculus, the prodrug becomes protonated and activated into Sulfenic Acid, which is rapidly converted to Sulfenamide. It is Sulfenamide that interacts with the proton pump, causing an irreversible inhibition. Although PPIs take up to 48 hours of treatment to see a strong inhibition of acid secretion, they are a very effective drug class. They can cause up to 90-95% inhibition of gastric acid secretions.

4. Compare the abilities of antacids which contain aluminum hydroxide, magnesium hydroxide, or calcium carbonate to interfere with normal GI tract function. Antacids are weak bases that react with gastric HCl to form a salt and water. Aluminum hydroxide and magnesium hydroxide react slowly with HCl to form AlCl or MgCl and water. These two agents are often administered together to counteract the constipation and diarrhea side effects. Calcium carbonate reacts slowly with HCl to form CO2 and CaCl2. The presence of the acid can cause belching or metabolic alkalosis. 5. What regions of the brain play important roles in regulating emesis? The emetic center is located in the medulla. The medulla is stimulated by many areas in the brain for the regulation of emesis. The higher brain centers are stimulated by memory, fear, dread, and anticipation from inside the CNS. From the periphery, the higher centers are stimulated by sensory input such as pain, smell and sight. The cerebellum is stimulated by the interaction of the inner ear (motion) and aminoglycosides with the H1 and M receptors. The solitary tract nucleus contains receptors for 5-HT3, D2, M, and H1. It is stimulated by blood-borne emetics stomach/SI  vagal and sympathetic afferents and by the pharynx (gagging) glossopharyngeal and trigeminal afferents. 6. Why is the CTZ region of the brain more susceptible than other brain regions to the effects of blood-borne antiemetics? The CTZ region of the brain is more susceptible to the effects of bloo-borne antiemetics because it is outside the BBB and is accessible to emetogenic stimuli in the blood or cerebrospinal fluid. 7. What other substances, in addition to protons, are secreted by parietal cells. On the luminal surface of the parietal cells there is a K+/Cl- channel. 8. Describe the relative ability of the different H2 antagonists to interfere with the metabolism of other drugs by cytochrome P450. Cimetidine, ranitidine, and famotidine undergo first-pass metabolism resulting in a bioavailability of approximately 50%. Nizatidine has little first-pass metabolism and a bioavailability of almost 100%. 9. When is the use of misoprostol contraindicated? Misoprostol is contraindicated in patients with IBS and also in patients that are pregnant. 10. Compare the effects of a D2 receptor antagonist, a 5HT3 receptor antagonist, and a 5HT4 receptor agonist on GI tract motility. D2 AT 5HT4 AG 5HT3 AT

↑ contraction, therefore ↑ motility

11. Compare the mechanisms of action of ondansetron, aprepitant, metoclopramide and dronabinol. (R = receptor) Example Antiemetic Class Type of Vomiting most effective against Ondansetron 5HT3 R AT -cytotoxic drug-induced emesis Aprepitant Neurokinin-R AT -cytotoxic drug-ind emesis (delayed vomiting) Metoclopramide D2 R AT -cytotoxic drug-induced emesis Dronabinol Cannabinoid R AG -cytotoxic drug-induced emesis 12. How could one discriminate between osmotic and secretory diarrhea? Secretory-↑ excretion of large amounts of water and electrolytes; ↓ absorption from GIT -osmolality = plasma osmolality Caused by: Cholera Tx-replenish body with water and salts Osmotic-poorly absorbed substances in lumen Caused by: malabsorption, lactose intolerance; Tx-fast to rid body of substance 13. What is the reason for adding atropine to preparations of diphenoxylate? Why is atropine not added to loperamide? Diphenoxylate causes some CNS effects and therefore has a higher potential for abuse. It is combine with atropine because atropine is a Ach AT which causes blurred vision and dry mouth. It was added so that people do not overdose on diphenoxylate, as increase diphenoxylate dose, increase atropine dose therefore increased atropine side effects. Loperamide has poor CNS penetration (LARGE doses may penetrate) therefore there is not much potential for abuse. 14. Compare the mechanism of saline laxatives, bulk forming laxatives, and stimulant laxatives. Saline (aka Osmotic laxatives)-osmotic retention of water stimulates peristalsis Bulk forming-indigestible, hydrophilic colloids that absorb water, forming a bulky, emollient gel that distends the colon and promotes peristalsis Stimulant-cause low-grade inflammation (retention of water and electrolytes) irritate lower portion of GIT, causing peristalsis 15. Describe the metabolites of sulfasalazine. Which metabolite is responsible for the adverse effects associated with sulfasalazine? Azo reductase breaks the Sulfasalazine azo bond, forming 5-ASA and Sulfapyridine. 5ASA is the therapeutically active agent but the presence of Sulfapyridine causes many potentially toxic side effects. Sulfapyridine undergoes extensive hepatic metabolism (P450 hydroxylation, acetylation, glucuronidation.) The side effects associated with Sulfapyridine include fever, fatigue, decreased folate absorption, and stimulation of allergic reactions (such as RBC hemolysis, rash and Steven’s Johnson syndrome.)