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Oropharynx and Hypopharynx
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The main functions of the mouth and oropharynx are chewing, lubrication of food with saliva, and swallowing. Saliva initiates digestion of starch by α-amylase (ptyalin), triglyceride digestion by lingual lipase, lubrication of ingested food by mucus, and protection of the mouth and esophagus by dilution and buffering of ingested foods.
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Saliva production is unique in that it is increased by both parasympathetic and sympathetic activity. Parasympathetic stimulation, via cranial nerves VII and IX, acts on muscarinic cholinergic receptors on acinar and ductal cells, increasing saliva production via vasodilation and increasing transport processes. Parasympathetic pathways are stimulated by food in the mouth, smells, conditioned reflexes, and nausea and are inhibited by sleep, dehydration, and fear. Sympathetic stimulation originates from preganglionic nerves in the thoracic segments T1 to T3. When β-adrenergic receptors are triggered by norepinephrine, production of saliva increases but at a rate less than that of parasympathetic stimulation.11 It is theorized that the hypersalivation, or sialorrhea, associated with clozapine use may be related to agonism of parasympathetic muscarinic receptors or antagonism of adrenergic α receptors (resulting in unopposed β-adrenergic receptor–mediated vasodilation).5 Conversely, dysfunction of saliva production, via the anticholinergic side effects of other antipsychotics, can lead to dry mouth, or xerostomia.
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The esophagus is a distensible muscular tube that extends from the epiglottis to the gastroesophageal junction. The lumen of the esophagus narrows at several points along its course, first at the cricopharyngeus muscle, then midway down alongside the aortic arch, and then distally where it crosses the diaphragm. The upper esophageal sphincter (UES) and lower esophageal sphincter (LES) are physiologic high-pressure regions that remain closed except during swallowing. Although the LES is a functional segment without anatomic features, the UES is marked by the presence of striated muscle.
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The wall of the esophagus reflects the general structural organization of the GI tract noted previously, consisting of mucosa, submucosa, muscularis propria, and adventitia. The mucosal layer has three components. The nonkeratinizing stratified squamous epithelial layer faces the lumen; provides protection for underlying tissue; and houses several specialized cell types such as melanocytes, endocrine cells, dendritic cells, and lymphocytes. The lamina propria is the nonepithelialized portion of the mucosa, and the muscularis mucosa, a layer of longitudinally oriented smooth muscle bundles, is the third component.
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The submucosa consists of loose connective tissue, and submucosal glands secrete a mucin-containing fluid via squamous epithelium-lined ducts, which facilitates lubrication of the esophageal lumen. The muscularis propria consists of an inner circular and outer longitudinal coat of smooth muscle; this layer also contains striated muscle fibers in the proximal esophagus that are responsible for voluntary swallowing.
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The esophagus has no serosal lining. Only small segments of the intra-abdominal esophagus are covered by adventitia, a sheathlike structure that also surrounds the adjacent great vessels, tracheobronchial tree, and other structures of the mediastinum.
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The esophagus provides a conduit for food and fluids from the pharynx to the stomach, and the sphincters generally prevent reflux of gastric contents into the esophagus. Normal transit of food involves coordinated motor activity, including a wave of peristaltic contraction, relaxation of the LES (facilitated by nitric oxide and VIP), and subsequent closure of the LES (facilitated by several hormones and neurotransmitters such as gastrin, acetylcholine, serotonin, and motilin). Xenobiotics can alter muscle tone in various segments of the esophagus, altering function. Caffeine is associated with relaxation of the LES and decreased peristalsis, increasing incidence of acid reflux.29 Additionally, sildenafil, via its effect on nitric oxide, relaxes esophageal smooth muscle, decreasing the pathologically elevated esophageal tone common to patients with achalasia.7 Because of the rapid transit time of swallowed substances through this portion of the GI tract, digestion does not take place, and passive diffusion of substances from the food into the bloodstream is prevented.11,46
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The stomach is a saccular organ covered entirely by peritoneum that has a capacity greater than 3 L. The stomach is divided into five anatomic regions: the cardia, fundus, corpus or body, antrum, and pyloric sphincter. The gastric wall consists of mucosa, submucosa, muscularis propria, and serosa. The interior surface of the stomach is marked by coarse rugae, or longitudinal folds. The mucosa is made up of a superficial epithelial cell compartment and a deep glandular compartment. The glandular compartment consists of gastric glands, which vary between regions of the stomach. The mucus glands of the cardia, fundus, and body secrete mucus and pepsinogen. Oxyntic, or acid-forming, glands found in the fundus and body contain parietal, chief, and endocrine cells. The parietal cells contain vesicles that house hydrochloric acid–secreting proton pumps and secrete intrinsic factor, a substance necessary for the ileal absorption of vitamin B12. Chief cells secrete the proteolytic proenzyme pepsinogen, which is cleaved to its active form, pepsin, upon exposure to the low luminal gastric pH of 3 to 4. Pepsin is subsequently inactivated in the duodenum when the pH increases to 6.0. The endocrine, or enterochromaffinlike (ECL), cells found in the mucosa of the body of the stomach produce histamine, which increases acid production and decreases gastric pH by stimulating H2 receptors on the parietal cells. Somatostatin and endothelin, both modulators of acid production, are also produced in ECL cells (Fig. 49–4).
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Hydrochloric acid is secreted when cephalic, gastric, and intestinal signals converge on the gastric parietal cells to activate proton pumps and release hydrochloric acid in an adenosine triphosphate–dependent process. During the cephalic phase, or the preparatory phase of the brain for eating and digestion, acetylcholine is released from vagal afferents in response to sight, smell, taste, and chewing. Acetylcholine stimulates the parietal cells via muscarinic receptors, resulting in an increase in cytosolic calcium and activation of the proton pump. G cells, located in the antrum of the stomach, produce and release gastrin in response to luminal amino acids and peptides. Gastrin activates receptors within parietal cells, leading to a similar increase in cytosolic calcium. Additionally, gastrin and vagal afferents induce the release of histamine from ECL cells, which stimulates parietal cell H2 receptors. Lastly, the intestinal phase is initiated when food containing digested protein enters the proximal small intestine and involves gastrin as well as a number of other polypeptides in the secretion of hydrochloric acid from the stomach46 (Fig. 20–3).
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The gastric mucosa is protected from gastric acidic secretions by several mechanisms, including a thin layer of surface mucus and channels that allow acid- and pepsin-containing fluids to exit glands without contact with the surface epithelium. Additionally, the surface epithelium secretes bicarbonate, raising the pH at the cell surface. Prostaglandins produced in the mucosal cells stimulate production of bicarbonate and mucus, and inhibit parietal cell production of acid; prostaglandin inhibition by nonsteroidal antiinflammatory drugs (NSAIDs) plays an important role in the pathogenesis of peptic ulcer disease.46
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In the stomach, ingested products are ground to particle sizes of less than 0.2 mm, which are then further processed and digested in preparation for absorption of nutrients in the small intestine. Many xenobiotics are weak acids that are no longer ionized in the acidic environment of the stomach, facilitating absorption through the lipid bilayer at the level of the stomach. Other factors that affect xenobiotic absorption include particle size, transit time, and type of drug delivery system. Different drug formulations, such as time release, enteric coating, slowly dissolving matrices, dissolution control via osmotic pumps, ion exchange resins, and pH-sensitive mechanisms, can affect bioavailability and the site of maximal release within the GI tract.
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The time required for gastric emptying is determined by the complex interplay of innervation, muscle action, underlying illness, and xenobiotic exposure. Digestion and absorption are time-dependent processes, and optimal absorption requires adjustment of the luminal environment through secretion of ions and water, to accommodate meals that vary considerably in nutrient composition, water content, and density. Osmoreceptors and chemoreceptors in the GI tract fine tune the digestive and absorptive processes by regulating transit and secretion using a variety of neurocrine, paracrine, and endocrine mechanisms. Interference with this integrated response may lead to stasis and bacterial overgrowth or rapid transit with decreased absorption and development of diarrhea. A large number of mediators affect motility, including common neurotransmitters, such as acetylcholine and norepinephrine; hormones; cytokines; inflammatory compounds; and others. In general, whereas parasympathetic impulses promote motility, sympathetic stimulation inhibits motility. Other transmitters, such as serotonin, promote transit, but dopamine and enkephalins can slow motility. Some xenobiotics, such as opioids and diphenhydramine, delay gastric emptying, but other xenobiotics, such as metoclopramide, may enhance gastric emptying. Our understanding of the complex neuroendocrine gastric axis continues to evolve in attempts to explain new phenomenon, such as the cannabinoid hyperemesis syndrome, which may be caused by cannabinoid receptors in the brain or gut.41
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Small and Large Intestines
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In an average adult, the small intestine is approximately 6 m in length and begins retroperitoneally as the duodenum, becoming intraperitoneal at the jejunum and ileum. The boundary between the small intestine and large intestine is the ileocecal valve, and the large intestine typically measures 1.5 m in an adult. The large intestine (or colon) is further divided into cecal, ascending, transverse, descending, and sigmoid segments. The sigmoid colon is continuous with the rectum and terminates at the anus. Whereas anterograde and retrograde peristalsis occurs in the small intestine, anterograde peristalsis predominates in the large intestine. This movement allows for mixing of food, maximizes contact with the mucosa, and is mediated by both the extrinsic and intrinsic nervous systems. The remarkable absorptive capacity of the small intestine is made possible by innumerable villi of the intestinal wall, which extend into the lumen and increase absorptive area. The epithelial border of the small intestine also contains mucin-secreting goblet cells, endocrine cells, and specialized absorptive cells; functionally, these cells create an ideal environment for nutrient absorption. The mucosa of the large intestine is devoid of villi. The large intestine functions primarily to absorb electrolytes and water, secrete potassium, salvage any remaining nutrients, and store and release waste. Intestinal epithelial cells also metabolize xenobiotics, a function typically attributed to the liver (see below).
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Regeneration of injured or senescent intestinal epithelial cells begins in the crypts, with differentiation occurring as these cells migrate toward the intestinal lumen. This process occurs rapidly, with turnover of the small intestinal epithelium occurring every 4 to 6 days and large intestinal epithelium turnover occurring every 3 to 8 days. This rapid regeneration leaves the intestinal epithelium vulnerable to processes that interfere with cell replication (eg, radiation, chemotherapy). Sloughing of GI epithelium, typically manifested by hemorrhagic enteritis, is a valuable marker for xenobiotic insults that lead to mitotic arrest.
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Anatomic and functional changes after bariatric surgery and bowel resection have important effects on drug bioavailability and toxicity. The common Roux-en-Y gastric bypass surgery, which diverts gastric contents into distal small bowel, may increase bioavailability by bypassing intestinal CYP3A or decrease bioavailability by bypassing the proximal jejunum as an area of drug absorption.16 Alterations in stomach and bowel pH after surgery may affect absorption of ionized drugs. Disruption of the enterohepatic recirculation may enhance elimination of drugs such as digoxin.48 Many xenobiotics, such as ethanol, oral morphine, and caffeine, achieve maximum serum concentrations faster because of rapid transit. However, studies evaluating serum concentrations of known CYP substrates (caffeine [CYP1A2], tolbutamide [CYP2C9], omeprazole [CYP219], and midazolam [CYP3A]) in patients with gastric bypass surgery have not found any clinically significant changes in drug metabolism.43 Because specific data are limited, current recommendations for dosing in postoperative patients are based on extrapolating from a xenobiotic site of absorption and kinetics and a particular patient’s functional GI anatomy.
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The pancreas is a retroperitoneal organ that serves both exocrine and endocrine functions. The exocrine portion of the gland produces digestive enzymes and occupies more than 80% to 85% of the mass of the pancreas. The exocrine pancreas is composed of acinar cells, specialized epithelial cells housing zymogen granules that release digestive enzymes and proenzymes into the duodenum. Columnar epithelial cells produce mucin and ductal cuboidal epithelial cells secrete a bicarbonate-rich fluid that neutralizes gastric acids. The pancreas secretes 2 to 2.5 L/day of this mixed solution. Typically, the digestive enzymes are released as proenzymes, such as trypsinogen, chymotrypsinogen, and procarboxypeptidase, which are activated upon contact with the higher pH of the duodenum; this process usually helps to prevent autodigestion of the pancreas itself. Enzymes on the brush border of the duodenum, including enteropeptidase, cleave proenzymes to their active forms. Only pancreatic amylase and lipase are secreted in their active forms.
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Secretion of pancreatic enzymes is regulated by multiple factors, the most important of which are cholecystokinin and secretin, both produced in the duodenum. Cholecystokinin is released from the duodenum in response to fatty acids and the products of protein catabolism such as peptides and amino acids. Cholecystokinin stimulates acinar cells to release digestive enzymes and proenzymes. Secretin is released by the duodenum in the presence of lowered pH caused by gastric acids and luminal fatty acids. Secretin triggers ductal cells to secrete bicarbonate and water. Acetylcholine also plays a role in the regulation of pancreatic exocrine function by stimulating digestive enzyme secretion from the acinus and potentiating the effects of secretin. Vagal reflexes increase acetylcholinergic tone in the setting of decreased pH, protein breakdown products, and fatty acids in the duodenal lumen.
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The endocrine portion of the pancreas is composed of approximately one million clusters of cells known as the islets of Langerhans that secrete insulin, glucagon, and somatostatin. Other products of the endocrine pancreas include serotonin and VIP. Injury to the endocrine pancreas can result in impaired glucose homeostasis. In one study, more than one third of patients with an episode of alcoholic pancreatitis subsequently developed impaired glucose tolerance.36