In this lecture we’re gonna cover the pharmacology of drugs acting on gastrointestinal system, so let’s get right into it. The gastrointestinal tract is a part of the human digestive system, which includes the mouth, esophagus, stomach, and intestines plus the accessory organs of digestion such as the salivary glands, pancreas, liver and gallbladder. Now, the nervous system, and endocrine system work together to control gastric secretions, and motility associated with the movement of food throughout the gastrointestinal tract.
Digestion starts with the sight, thought, or smell of food. When the brain anticipates an incoming meal, the vagus nerve sends a message to the stomach to stimulate gastric secretion. The mucosal lining of the stomach contains numerous gastric glands.
These glands open to the surface of the mucosa through tiny holes called gastric pits. There are few different types of cells that make up the gastric glands: Surface and neck mucous cells which produce jelly-like substance called mucous that protects the lining of the stomach; Parietal cells which produce hydrochloric acid that creates a low pH environment in the stomach; Chief cells which produce pepsinogen and gastric lipase, enzymes that are responsible for digestion of dietary proteins and fat; Enterochromaffin-like (ECL) cells which produce histamine that helps to induce the production of acid; and G-cells which produce peptide hormone gastrin that is responsible for regulation of gastric activity. Now, the vagus nerve is the single neural link between the brain's higher functions and gastric secretion.
In response to food intake vagus nerve becomes excited and begins to release acetylcholine. Acetylcholine (ACh) exerts its effects in the stomach directly, through activation of muscarinic M3 receptors on parietal cells, as well as indirectly, through activation of M1 receptors on enterochromaffin-like (ECL) cells to initiate histamine release, and M3 receptors on G cells to initiate gastrin release. Subsequently, parietal cells are stimulated by histamine via H2 receptors, and by gastrin which acts on ECL cell’s cholecystokinin (CCK) B receptors to enhance the histamine release in addition to directly stimulating parietal cells which also express cholecystokinin (CCK) B receptors.
Now the activation of H2 receptor by histamine causes intracellular cAMP levels to increase while the activation of M3 receptor by acetylcholine and cholecystokinin B (CCK-B) receptor by gastrin causes intracellular calcium levels to increase. These independent pathways then converge to activate protein kinase cascade that in turn triggers translocation of hydrogen-potassium-ATPase (H+/K+ ATPase) also known as the proton pump, from cytoplasm to the apical surface. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for the active transport of hydrogen ions out of the cell in exchange for potassium ions.
Chloride ions are also secreted from parietal cells into the lumen by simple diffusion. In the stomach lumen H+, Cl−, and water combine to form hydrochloric acid (HCl) which creates a highly acidic environment for digestion. Now, understanding the physiology of gastric acid secretion and the pathophysiology of acid-related diseases such as gastrooesophageal reflux and peptic ulcer has led to the development of various ways to decrease acid exposure.
One of the pharmacological approaches aimed at neutralizing secreted acid is to prevent stimulation of the parietal cell. This can be achieved with the use of drugs called H2-receptor antagonists, which work by competitively inhibiting histamine binding at H2 receptors on the parietal cells, resulting in reduction of histamine-mediated acid secretion. Drgs that belong to this class include Cimetidine, Famotidine, Nizatidine and Ranitidine.
Now another pharmacological approach is to directly disrupt the functioning of the proton pump responsible for acid secretion. This can be achieved with the use of drugs called proton-pump inhibitors, which work by binding to the hydrogen-potassium-ATPase (H+/K+ ATPase) and suppressing the secretion of hydrogen ions into the gastric lumen. Drgs that belong to this class include Dexlansoprazole, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, and Rabeprazole.
All right, so while H2-receptor antagonists and proton-pump inhibitors can provide a sustained suppression of gastric acid secretion, patients needing immediate relief from their symptoms may benefit from a faster acting agents belonging to a drug class known as non-systemic antacids. Members of this class include aluminum hydroxide [Al(OH)3], magnesium hydroxide [Mg(OH)2], and Calcium carbonate [CaCO3]. Unlike the other acid-reducing agents, non-systemic antacids do not decrease acid secretion but instead act primarily by directly neutralizing hydrochloric acid.
This happens as a result of simple chemical reaction that combines a metal ion from an antacid compound (Al, Ca, Mg) with a gastric acid binding group (Cl) to form a salt and water. This in turn raises the pH of the stomach contents and provides rapid relief from hyperacidity. All right, so in addition to neutralizing acid or inhibiting its secretion, patients suffering from gastric ulcers can also benefit from a mucosal protective agents.
In order to understand how these agents work, lets go back to our illustration of acid-secreting parietal cell. First, there are some important details that need to be added here. So the reason why histamine stimulates cAMP production is because the activity of H2 receptor is mediated by stimulatory Gs protein which activates adenylyl cyclase, the enzyme that synthesizes cAMP from ATP.
Furthermore parietal cells also express E-type prostaglandin receptors linked to an inhibitory Gi protein, which when stimulated by prostaglandins such as prostaglandin E1 (PGE1), inhibit the activation of adenyl cyclase. Now, Misoprostol is a synthetic prostaglandin E1 analog that stimulates prostaglandin receptors on parietal cells to decrease intracellular cAMP levels, thus leading to decreased activity of the hydrogen-potassium-ATPase (H+/K+ ATPase). In addition to this, Misoprostol also increases gastric mucus formation as well as blood flow to the mucosa, which increases the oxygen and nutrient supply to the injured mucosa, thus promoting healing.
Sucralfate, on the other hand, is a complex of aluminum hydroxide and sulfated sucrose molecules which in acidic environment of the stomach, breaks down into strongly negatively charged sucrose sulfate and aluminum salt. The negatively charged sucrose sulfate then binds to positively charged proteins in the base of erosion, forming a physical barrier that restricts further damage allowing ulcers to heal more rapidly. All right, now that we discussed agents used in treatment of peptic ulcers and gastro-esophageal reflux disease, let’s move on to discuss agents used in another common GI related malady that is nausea and vomiting.
So, nausea and vomiting occurs when an area of the medulla called the vomiting centre is stimulated by the central and peripheral neural pathways. When stimulated, the vomiting centre initiates and controls the act of vomiting, which involves a series of contractions of the smooth muscles lining the digestive tract. Now, the vomiting centre receives stimulatory signals from four major neural pathways: the chemoreceptor trigger zone located near the vomiting center, which expresses receptors such as dopamine D2, serotonin type-3 (5-HT3) and neurokinin-1 (NK-1); the vagal afferent fibers from the gastrointestinal system, which express serotonin type-3 (5-HT3) and neurokinin-1 (NK-1) receptors; the central vestibular nuclei, which express muscarinic and histamine H1 receptors; and lastly the higher centres of the brain.
Now the signals from each of these emetic areas can be generated in response to various stimuli. For example; chemoreceptor trigger zone can be stimulated by circulating medications and toxins which directly or indirectly stimulate dopamine D2 receptors. This is the reason why many chemotherapeutic drugs can cause nausea and vomiting; now, this mechanism can be counteracted by medications such as, Chlorpromazine, Prochlorperazine and Metoclopramide, which act by blocking dopamine D2 receptors in the chemoreceptor trigger zone thus inhibiting stimulatory effects of dopamine.
Next we have enterochromaffin cells of the gastrointestinal tract that can also be stimulated by ingested irritants or toxins, which in turn cause them to release neurotransmitters serotonin and substance P that bind to their respective receptors to send the signal to the chemoreceptor trigger zone. This mechanism can be counteracted by medication such as Ondansetron, which acts by blocking serotonin type-3 (5-HT3) receptors on vagal afferent nerves and chemoreceptor trigger zone thus inhibiting stimulatory effects of serotonin. Furthermore, in treatment of chemotherapy-induced nausea and vomiting, in order to enhance antiemetic effects, Ondansetron is often given with other medications such as Aprepitant and Rolapitant, which work by blocking neurokinin-1 (NK-1) receptors thus inhibiting stimulatory effects of substance P.
Finally we have the vestibular nucleus, which receives input from the vestibular system of the inner ear that is sensitive to changes in balance and motion; hence unexpected or conflicting sensory signals concerning body orientation in space can stimulate vestibular nerves to release histamine and acetylcholine that in turn stimulate receptors of the vestibular nucleus and send signal to the vomiting center causing motion sickness; this mechanism can be counteracted by anticholinergic medication such as Scopolamine, which blocks the muscarinic receptors, as well as antihistamines such as Diphenhydramine, Dimenhydrinate, Meclizine and Promethazine, which block both histamine H1 and muscarinic receptors thus inhibiting stimulatory effects of acetylcholine and histamine. All right moving on to the next common gastrointestinal disorder that is constipation. So, constipation occurs when bowel movements become less frequent and stools become more difficult to pass.
Laxatives are a group of drugs commonly used to relieve constipation by loosening stools or inducing a bowel movement. There are several types of laxatives with somewhat different mechanism of action. One of the most commonly used are bulk laxatives, which are insoluble and nonabsorbable cellulose fibers that expand on taking up water in the large intestine thus forming a large mass.
This mass causes distention of the intestinal wall which in turn activates mechanoreceptors that induce neuronally mediated contraction and relaxation of intestinal smooth muscle causing the stool to move along. Bulk laxatives include natural fiber supplements such as Psyllium as well as synthetic fibers such as Methylcellulose and Calcium Polycarbophil. Another type of commonly used laxatives are osmotic laxatives.
These include nonabsorbable but soluble compounds such as Magnesium Citrate, Magnesium Hydroxide, Lactulose, and Polyethylene Glycol. Once these agents enter the intestine, the concentration of solutes increase, causing water to pull in to the colon through osmosis. The water then increases stool volume and stretches the wall of the bowel, triggering defecation reflex.
The last most commonly used type of laxatives are irritants and stimulants. Laxatives in this group act by variety of mechanisms. Some stimulant laxatives directly prevent water reabsorption in the colon as well as promote water secretion from the intestinal cells into the lumen.
Others irritate nerve fibers in the intestinal mucosa thus triggering defecation reflex. Agents that belong to this group include Bisacodyl, Castor oil, and Senna. All right, now before we end let’s discuss one more common disorder affecting gastrointestinal tract that is diarrhea.
So if constipation is characterized by infrequent and hard stools, diarrhea can be thought of as the opposite. Patients with diarrhea experience loose, watery and typically more-frequent bowel movements. Now, depending on the underlying pathophysiology, diarrhea can be classified as secretory, osmotic, or inflammatory.
Secretory diarrhea typically results from bacterial toxins that inhibit the ability of enterocytes to absorb sodium chloride (NaCl) and water, and stimulate fluid secretion into the intestinal lumen. Osmotic diarrhea occurs due to ingestion of poorly absorbable substances such as rehydration solutions containing salts and glucose, which osmotically pull water into the bowel lumen. Finally, inflammatory diarrhea occurs when infectious microbes or autoimmunity cause damage to the mucosal lining or brush border which in turn causes fluids to leak from the cells into the intestine.
Now there are few drugs that can be used to treat diarrhea. Among them are; adsorbent agents such as Methylcellulose, which work by absorbing toxins that are stimulating gut motility and secretions; and Antimotility agents such as Diphenoxylate and Loperamide, which work by binding to the opiate receptor in the gut wall to inhibit the release of acetylcholine and prostaglandins. This in turn slows down the movement of intestinal muscle and increases the amount of time it takes for the byproducts of digestion to move through the intestine.
One notable difference between these two agents is their ability to cross blood-brain-barrier. Loperamide cannot cross the blood brain barrier to cause CNS effects, therefore it has low abuse potential. In contrast, Diphenoxylate can cross the blood brain barrier, so it is usually combined with Atropine to prevent drug abuse.
Lastly, we have Bismuth Subsalicylate, which works by inhibiting replication of certain bacteria and viruses as well as reducing inflammation and decreasing the flow of fluids and electrolytes into the bowel. And with that, I wanted to thank you for watching I hope you enjoyed this video and as always stay tuned for more.
