DRUGS AFFECTING GASTROINESTINAL SYSTEM AND NUTRITION
Drugs for Gastric and Duodenal Ulcers
In the area of a gastric or duodenal peptic ulcer, the mucosa has been attacked by digestive juices to such an extent as to expose the subjacent connective tissue layer (submucosa).
This self-digestion occurs when the equilibrium between the corrosive hydrochloric acid and acid-neutralizing mucus, which forms a protective cover on the mucosal surface, is shifted in favor of hydrochloric acid. Mucosal damage can be promoted by Helicobacter pylori bacteria that colonize the gastric mucus. Drugs are employed with the following therapeutic aims: (1) to relieve pain; (2) to accelerate healing; and (3) to prevent ulcer recurrence.
Herapeutic approaches are threefold: (a) to reduce aggressive forces by lowering H+ output; (b) to increase protective forces by means of mucoprotectants; and (c) to eradicate Helicobacter pylori.
I. Drugs for Lowering Acid Concentration
Ia. Acid neutralization. H+-binding groups such as CO3 2–, HCO3 – or OH–, together with their counter ions, are contained in antacid drugs.
Neutralization reactions occurring after intake of CaCO3 and NaHCO3, respectively, are shown in (A) at left. With nonabsorbable antacids, the counter ion is dissolved in the acidic gastric juice in the process of neutralization. Upon mixture with the alkaline ncreatic secretion in the duodenum, it is largely precipitated again by basic groups, e.g., as CaCO3 or AlPO4, and excreted in feces. Therefore, systemic absorption of counter ions or basic residues is minor. In the presence of renal insufficiency, however, absorption of even small amounts may cause an increase in plasma levels of counter ions (e.g., magnesium intoxication with paralysis and cardiac disturbances). Recipitation in the gut lumen is responsible for other side effects, such as reduced absorption of other drugs due to their adsorption to the surface of precipitated antacid or, phosphate depletion of the body with excessive intake of Al(OH)3. Na+ ions remain in solution even in the presence of HCO3 –-rich pancreatic secretions and are subject to absorption, like HCO3 –. Because of the uptake of Na+, use of NaHCO3 must be avoided in conditions requiring restriction of NaCl intake, such as hypertension, cardiac failure, and edema. Since food has a buffering effect, antacids are taken between meals (e.g., 1 and 3 h after meals and at bedtime). Nonabsorbable antacids are preferred. Because Mg(OH)2 produces a laxative effect (cause: osmotic action, release of cholecystokinin by Mg2+, or both) and Al(OH)3 produces constipation (cause: astringent action of Al3+), these two antacids are frequently used in combination.
Historically, these drugs have been the mainstay of treatment for acid-related disorders. With the development of more effective pharmaceutical agents, they’ve become less popular. Nevertheless, their sales continue to generate significant income (Tums generated $140 million in 2004). The very water-soluble NaHCO3 is rapidly cleared from the stomach and presents both an alkali and a sodium load. CaCO3 caeutralize HCl rapidly and effectively; however, it can cause abdominal distention and belching. Combinations of Mg2+ and Al3+ hydroxides provide a relatively fast and sustained neutralizing capacity. Magaldrate is a hydroxymagnesium aluminate complex that is rapidly converted in gastric acid to Mg(OH)2 and Al(OH)3, which are poorly absorbed and thus provide a sustained antacid effect with balanced effects on intestinal motility. Simethicone, a surfactant that may decrease foaming and hence esophageal reflux, is included in many antacid preparations. The presence of food alone elevates gastric pH to about 5 for approximately 1 hour and prolongs the neutralizing effects of antacids for about 2 hours. Alkalinization of the gastric contents increases gastric motility, through the action of gastrin. Al3+ can relax gastric smooth muscle, producing delayed gastric emptying and constipation, effects that are opposed by those of Mg2+. Thus, Al(OH)3 and Mg(OH)2 taken concurrently have relatively little effect on gastric emptying or bowel function. Because of its capacity to enhance secretion and to form insoluble compounds, CaCO3 has unpredictable effects on gastrointestinal motility. The release of CO2 from bicarbonate and carbonate-containing antacids can cause belching, occasional nausea, abdominal distention, and flatulence.
Antacids are cleared from the empty stomach in about 30 minutes and vary in the extent to which they are absorbed. Antacids that contain aluminum, calcium, or magnesium are less completely absorbed than are those that contain NaHCO3. In persons with normal renal function, the modest accumulations of Al3+ and Mg2+ do not pose a problem; with renal insufficiency, however, absorbed Al3+ can contribute to osteoporosis, encephalopathy, and proximal myopathy. About 15% of orally administered Ca2+ is absorbed, causing a transient hypercalcemia. Although not a problem iormal patients, the hypercalcemia from as little as 3 to
Ib. Inhibitors of acid production. Acting on their respective receptors, the transmitter acetylcholine, the hormone gastrin, and histamine released intramucosally
stimulate the parietal cells of the gastric mucosa to increase output of HCl. Histamine comes from enterochromaffin– like (ECL) cells; its release is stimulated by the vagus nerve (via M1 receptors) and hormonally by gastrin. The effects of acetylcholine and histamine can be abolished by orally applied antagonists that reach parietal cells via
the blood. The cholinoceptor antagonist pirenzepine, unlike atropine, prefers holinoceptors of the M1 type, does not penetrate into the CNS, and thus produces fewer atropine-like side effects The cholinoceptors on parietal cells probably belong to the M3 subtype. Hence, pirenzepine may act by blocking M1 receptors on ECL cells or submucosal neurons. Histamine receptors on parietal cells belong to the H2 type and are blocked by H2-antihistamines.
Four different H2-receptor antagonists (H2RAs) are currently on the market in the
The most prominent effects of H2RAs are on basal acid secretion; less profound but still significant is suppression of stimulated (feeding, gastrin, hypoglycemia, or vagal stimulation) acid production. These agents thus are particularly effective in suppressing nocturnal acid secretion, which reflects mainly basal parietal cell activity. This fact has clinical relevance in that the most important determinant of duodenal ulcer healing is the level of nocturnal acidity. In addition, some patients with reflux esophagitis who are being treated with PPIs may continue to produce acid at night (so-called nocturnal acid breakthrough) and could benefit from the addition of an H2RAs at night.
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H2RAs are absorbed rapidly after oral administration, with peak serum concentrations reached within 1-3 hours. Unlike PPIs, only a small percentage of H2RAs is protein-bound. Small amounts of these drugs undergo metabolism in the liver. Both metabolized and unmetabolized products are excreted by the kidney by both filtration and renal tubular secretion. It is important to reduce doses of H2RAs in patients with renal and in advanced liver disease. All four H2RAs are available in dosage forms for oral administration; intravenous and intramuscular preparations of cimetidine, ranitidine, and famotidine also are available. Therapeutic levels are achieved quickly after intravenous dosing and are maintained for several hours (4 to 5 hours for cimetidine, 6 to 8 hours for ranitidine, and 10 to 12 hours for famotidine). In clinical practice, these drugs can be given in intermittent boluses or by continuous infusion. The overall incidence of adverse effects of H2-receptor antagonists is low (<3%). Side effects usually are minor and include diarrhea, headache, drowsiness, fatigue, muscular pain, and constipation. Less-common side effects include those affecting the CNS (confusion, delirium, hallucinations, slurred speech, and headaches), which occur primarily with intravenous administration of the drugs. Gynecomastia in men and galactorrhea in women may occur due to the binding of cimetidine to androgen receptors and inhibition of the cytochrome P450-catalyzed hydroxylation of estradiol. H2RAs have been associated with thrombocytopenia. H2-receptor antagonists cross the placenta and are excreted in breast milk. Although no major teratogenic risk has been associated with these agents, caution is nevertheless warranted when they are used in pregnancy. All agents that inhibit gastric acid secretion may alter the rate of absorption and subsequent bioavailability of the H2RAs. Drug interactions with H2RAs can be expected mainly with cimetidine, and these are an important factor in the preferential use of other H2-receptor antagonists. Cimetidine inhibits cytochrome P450 more so than do the other agents in this class and can thereby alter the metabolism and increase the levels of drugs that are substrates for the cytochrome P450 system.
Because histamine plays a pivotal role in the activation of parietal cells, H2-antihistamines also diminish responsivity to other stimulants, e.g., gastrin (in gas- trin-producing pancreatic tumors, Zollinger-Ellison syndrome). Cimetidine, the first H2-antihistamine used therapeutically, only rarely produces side effects (CNS disturbances such as confusion; endocrine effects in the male, such as gynecomastia, decreased libido, impotence). Unlike cimetidine, its newer and more potent congeners, ranitidine, nizatidine, and famotidine, do not interfere with the hepatic biotransformation of other drugs. Omeprazole can cause maximal inhibition of HCl secretion. Given orally in gastric juice-resistant capsules, it reaches parietal cells via the blood. In the acidic milieu of the mucosa, an active metabolite is formed and binds covalently to the ATP-driven proton pump (H+/K+ ATPase) that transports H+ in exchange for K+ into the gastric juice. Lansoprazole and pantoprazole produce analogous effects. The proton pump inhibitors are first-line drugs for the treatment of gastroesophageal reflux disease.
Proton Pump Inhibitors The most effective suppressors of gastric acid secretion are the gastric H+,K+-ATPase (proton pump) inhibitors. Current proton pump inhibitors (PPIs) on the market include: omeprazole (PRILOSEC), lansoprazole (PREVACID), rabeprazole (ACIPHEX), and pantoprazole (PROTONIX).
They arepyridylmethylsulfinyl benzimidazoles with different substitutions on the pyridine or the benzimidazole groups. PPIs are “prodrugs,” requiring activation in an acid environment.
These agents enter the parietal cells from the blood stream and accumulate in the acidic secretory canaliculi of the parietal cell, where they are activated by a proton-catalyzed process that results in the formation of a thiophilic sulfenamide or sulfenic acid. This activated form reacts by covalent binding with the sulfhydryl group of cysteines from the extracellular domain of the H+,K+-ATPase. Binding to cysteine
Secretion of acid resumes only after new molecules of the pump are inserted into the luminal membrane.PPIs are unstable at a low pH. The oral dosage forms (“delayed release”) are supplied as enteric-coated granules encapsulated in a gelatin shell (omeprazole and lansoprazole) or as enteric-coated tablets (pantoprazole and rabeprazole). The granules dissolve only at an alkaline pH, thus preventing degradation of the drugs by acid in the esophagus and stomach. PPIs are rapidly absorbed, highly protein bound, and extensively metabolized in the liver by the cytochrome P450 system (particularly CYP2C19 and CYP3A4). Their sulfated metabolites are excreted in the urine or feces. Their plasma half-lives are about 1 to 2 hours, but their durations of action are much longer. Chronic renal failure and liver cirrhosis do not appear to lead to drug accumulation with once-a-day dosing of the drugs.
Hepatic disease reduces the clearance of lansoprazole substantially, and dose reduction should be considered in patients with severe hepatic disease. The requirement for acid to activate these drugs within the parietal cells has several important consequences. The drugs should be taken with or before a meal, since food will stimulate acid production by parietal cells; conversely, coadministration of other acid-suppressing agents such as H2-receptor antagonists may diminish the efficacy of proton pump inhibitors. Since not all pumps or all parietal cells are functional at the same time, it takes several doses of the drugs to result in maximal suppression of acid secretion. With once-a-day dosing, steady-state inhibition, affecting about 70% of pumps, may take 2 to 5 days. Since the binding of the drugs’ active metabolites to the pump is irreversible, inhibition of acid production will last for 24 to 48 hours or more, until new enzyme is synthesized. The duration of action of these drugs, therefore, is not directly related to their plasma half-lives. PPIs inhibit the activity of some hepatic cytochrome P450 enzymes and therefore may decrease the clearance of benzodiazepines, warfarin, phenytoin, and many other drugs. PPIs usually cause few adverse effects (<3%); nausea, abdominal pain, constipation, flatulence, and diarrhea are the most common side effects.
Subacute myopathy, arthralgias, headaches, and skin rashes also have been reported. Chronic treatment with PPI’s decreases the absorption of vitamin B12, but insufficient data exist to demonstrate whether or not this leads to a clinically relevant deficiency. Hypergastrinemia (>500 ng/liter) occurs in approximately 5% to 10% of long-term PPI users. Gastrin is a trophic factor for epithelial cells, and there is a theoretical concern that elevations in gastrin can promote the growth of different kinds of tumors in the gastrointestinal tract. In rats undergoing long-term administration of proton pump inhibitors, there has been development of enterochromaffin-like cell hyperplasia and gastric carcinoid tumors secondary to sustained hypergastrinemia; this has raised concerns about the possibility of similar complications in human beings. There are conflicting data on the risk and clinical implications of enterochromaffin-like cell hyperplasia in patients on long-term proton pump inhibitor therapy. These drugs now have a track record of more than 15 years of use worldwide, and no major new issues regarding safety have emerged. PPI’s have not been associated with a major teratogenic risk when used during the first trimester of pregnancy; caution, however, is still warranted.
II. Protective Drugs Sucralfate (A) contains numerous aluminum hydroxide residues. However, it is not an antacid because it fails to lower the overall acidity of gastric juice. After oral intake, sucralfate molecules undergo cross-linking in gastric juice, forming a paste that adheres to mucosal defects and exposed deeper layers. Here sucralfate intercepts H+. Protected from acid, and also from pepsin, trypsin, and bile acids, the mucosal defect can heal more rapidly. Sucralfate is taken on an empty stomach (1 h before meals and at bedtime). It is well tolerated; however, released Al3+ ions can cause constipation.
In the presence of acid-induced damage, pepsin-mediated hydrolysis of mucosal proteins contributes to mucosal erosion and ulcerations. This process can be inhibited by sulfated polysaccharides. Sucralfate (CARAFATE) consists of the octasulfate of sucrose to which aluminum hydroxide has been added. In an acid environment (pH < 4), it undergoes extensive cross-linking and polymerization to produce a viscous, sticky gel that adheres strongly to epithelial cells and even more strongly to ulcer craters for as long as 6 hours after a single dose. In addition to inhibition of hydrolysis of mucosal proteins by pepsin, sucralfate may have additional cytoprotective effects, including stimulation of local production of prostaglandin and epidermal growth factor. Sucralfate also binds bile salts, accounting for its use in some patients with esophagitis or gastritis in whom reflux of bile is thought by some to play a role in pathogenesis. The role of sucralfate in the treatment of acid-peptic disease clearly has diminished in recent years. It still may be useful in the prophylaxis of stress ulcers, where its use may be associated with a lower incidence of nosocomial pneumonia compared to acid-suppressing therapy with its tendency to promote gastric bacterial colonization. Since it is activated by acid, it is recommended that sucralfate be taken on an empty stomach one hour before meals rather than after; the use of antacids within 30 minutes of a dose of sucralfate should be avoided.
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The most commonly reported side effect is constipation (2%). Small amounts of aluminum can be absorbed with the use of sucralfate, and special attentioeeds to be given to patients with renal failure, who are at risk for aluminum overload. Aluminum-containing antacids should not be used with sucralfate in patients with renal failure. Since sucralfate forms a viscous layer in the stomach, it may inhibit absorption of other drugs and change their bioavailability. These include phenytoin, digoxin, cimetidine, ketoconazole, and fluoroquinolone antibiotics. It is therefore recommended that sucralfate be taken at least 2 hours after the intake of other drugs.
Misoprostol (B) is a semisynthetic prostaglandin derivative with greater stability thaatural prostaglandin, permitting absorption after oral administration. Like locally released prostaglandins, it promotes mucus production and inhibits acid secretion. Additional systemic effects (frequent diarrhea; risk of precipitating contractions of the gravid uterus) significantly restrict its therapeutic utility.
Prostaglandins PGE2 and PGI2, the major prostaglandins synthesized by gastric mucosa, inhibit acid production by binding to the EP3 receptor on parietal cells. Prostaglandin binding to the receptor results in inhibition of adenylyl cyclase and decreased levels of intracellular cyclic AMP. PGE also can prevent gastric injury by its so-called cytoprotective effects, which include stimulation of secretion of mucin and bicarbonate and improvement in mucosal blood flow; however, acid suppression appears to be its more critical effect. Since NSAIDs inhibit prostaglandin formation, the synthetic prostaglandins provide a rational approach to reducing NSAID-related mucosal damage.
Misoprostol (15-deoxy-16-hydroxy-16-methyl-PGE1; CYTOTEC) is a synthetic analog of prostaglandin E1 with an additional methyl ester group at C1 (resulting in an increase in potency and in the duration of the antisecretory effect) and a switch of the hydroxy group from C15 to C16 along with an additional methyl group (resulting in improved activity and duration of action). The degree of inhibition of gastric acid secretion by misoprostol is directly related to dose; oral doses of 100 to 200 ug produce significant inhibition of basal acid secretion (decreased by 85% to 95%) or food-stimulated acid secretion (decreased by 75% to 85%).
Misoprostol is rapidly absorbed and undergoes extensive and rapid first-pass metabolism (deesterification) to form misoprostol acid (the free acid), the principal and active metabolite of the drug. Some of this conversion may in fact occur in the parietal cells. After a single dose, inhibition of acid production can be seen within 30 minutes, peaks at 60 to 90 minutes, and lasts for up to 3 hours. Food and antacids decrease the rate of absorption of misoprostol, resulting in delayed and decreased peak plasma concentrations of misoprostol acid. The elimination half-life of the free acid, which is excreted mainly in the urine, is about 20 to 40 minutes.
Carbenoxolone (B) is a derivative of glycyrrhetinic acid, which occurs in the sap of licorice root (succus liquiritiae). Carbenoxolone stimulates mucus production.
At the same time, it has a mineralocorticoid-like action (due to inhibition of 11-β–hydroxysteroid dehydrogenase) that promotes renal reabsorption of NaCl and water. It may, therefore, exacerbate hypertension, congestive heart failure, or edemas. It is
obsolete.
u Helicobacter pylori
III. Eradication of Helicobacter pylori C. This microorganism plays an important
role in the pathogenesis of chronic gastritis and peptic ulcer disease.
The combination of antibacterial drugs and omeprazole has proven effective. In case of intolerance to amoxicillin or clarithromycin, metronidazole can be used as a substitute. Colloidal bismuth compounds are also effective; however, the problem of heavy-metal exposure compromises their long-term use.
Gastroesophageal Reflux Disease
The goals of GERD therapy are complete resolution of symptoms and healing of esophagitis. PPIs are clearly more effective than H2-RAs in achieving both of these goals. Healing rates after 4 weeks and 8 weeks of therapy with PPIs are around 80% and 90%, respectively; healing rates with H2-RAs are 50% and 75%. Indeed, PPIs are so effective that their empirical use has been advocated as a therapeutic trial in patients in whom GERD is suspected to play a role in the pathogenesis of symptoms. A diagnostic work up is instituted only if such a trial fails. Because of the wide clinical spectrum associated with GERD, the therapeutic approach is best tailored to the level of severity in the individual patient. In general, the optimal dose for each individual patient should be determined based upon symptom control. Only in patients with complicated GERD and/or Barrett’s esophagus is documentation of complete acid control with 24-hour pH monitoring indicated. Although some patients with mild GERD symptoms may be managed by nocturnal doses of H2RAs, dosing two or more times a day generally is required. In patients with severe symptoms or extraintestinal manifestations of GERD, twice-daily dosing with a PPI may be needed. It has been shown, though, that nocturnal acid breakthrough can occur even with twice-daily PPI dosing in healthy subjects and thus this may be controlled by the addition of an H2RA at bedtime. A popular approach to GERD therapy consists of a “step-up” regimen, beginning with an H2RA and only progressing to one of the proton pump inhibitors if symptoms fail to respond. (Indeed many insurance provides will not allow PPI dispensing without first a trial of an H2RA). Conversely, once symptoms are controlled over a period of time, “step-down” therapy is recommended (i.e. stepping down from a PPI to an H2RA and from H2RAs to antacids).
Patients should be treated with the least aggressive acid-suppressive regimen that completely controls their symptoms. Antacids currently are recommended only for the patient with mild, infrequent episodes of heartburn. Their use, of course, is entrenched in the public mind, and it is rare for a patient with GERD not to have tried several of these medications before seeking medical help.
The pathophysiology of peptic ulcer disease (PUD) is best understood in terms of an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, nitric oxide, other peptides and growth factors) and aggravating factors (acid and pepsin). Patients with duodenal ulcers on average produce more acid than do control subjects, particularly at night (basal secretion). Although patients with gastric ulcers have normal or even lower acid production than control subjects, ulcers rarely if ever occur in the complete absence of acid. In these gastric ulcer patients, even the lower levels of acid can produce injury, presumably due to weakened mucosal defense and reduced bicarbonate production. Both H. pylori and exogenous agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) interact with these factors in complex ways, leading to an ulcer diathesis. Up to 80% to 90% of ulcers may be associated with H. pylori infection of the stomach. This infection may lead to impaired production of somatostatin by D cells and, in time, decreased inhibition of gastrin production, with a resulting higher acid production as well as impaired duodenal bicarbonate production. NSAIDs also are very frequently associated with peptic ulcers (in up to 60% of patients, particularly those with complications such as bleeding). Topical injury by the luminal presence of the drug appears to play a minor role in the pathogenesis of these ulcers, as evidenced by the fact that ulcers can occur with very low doses of aspirin (10 mg) or with parenteral administration of NSAIDs. The effects of these drugs are instead mediated systemically, with the critical element being suppression of the constitutive form of cyclooxygenase (COX)
Despite such studies and the results of meta-analysis, the benefits from empiric acid-suppressive therapy in patients with acute gastrointestinal bleeding remain somewhat controversial. Although PPIs are probably more effective than H2RAs in this setting, the availability of intravenous preparations of H2-receptor antagonists has led to their widespread use. This practice has since be replaced by intravenous proton pump inhibitors. H. pylori, a gram-negative rod, has been associated with gastritis and subsequent development of gastric and duodenal ulcers, gastric adenocarcinoma and gastric B-cell lymphoma. Because of its critical role in the pathogenesis of peptic ulcers in the majority of cases, it has become standard care to eradicate this infection in patients with gastric or duodenal ulcers. Such a strategy almost completely eliminates the risk of ulcer recurrence, provided patients are not taking NSAIDs. Eradication of H. pylori also is indicated in the treatment of MALT-lymphoma of the stomach, as this can regress significantly after such treatment. Treatment of H. pylori infection often requires a week course of “triple therapy”(two antibiotics and an acid suppressing agent) (Figure 10). Single antibiotic regimens are ineffective and lead to resistance. A PPI or H2RA significantly enhances the effectiveness of regimens containing pH-dependent antibiotics such as amoxicillin or clarithromycin, and an extended, 14 day, course of treatment appears to be most efficacious. Antibiotic resistance is increasingly being recognized as an important factor in the failure to eradicate H. pylori. Antibiotic resistance is a complex issue, with different underlying mechanisms and clinical implications. Clarithromycin resistance is related to ribosomal mutations that prevent the binding of the antibiotic and is an all-or-none phenomenon. On the other hand, metronidazole resistance is relative rather than absolute and may involve several different changes in the bacteria.
NSAID-Related Ulcers
Chronic NSAID users have a 2% to 4% risk of developing a symptomatic ulcer, gastrointestinal bleeding, or even perforation. Ulcer healing despite continued NSAID use is possible with the use of acid-suppressant agents, usually at higher doses and for a considerably longer duration than with standard regimens (e.g., 8 weeks or longer). Again, PPIs are superior to H2RAs and misoprostol in promoting healing of active ulcers (80% to 90% healing rates compared to 60% to 75%) as well as in preventing recurrence (while on NSAIDs) of both gastric ulcers (5% to 13% versus 10% to 16% recurrence rates) and duodenal ulcers (0.5% to 3% versus 4% to 10% recurrence rate).
Zollinger-Ellison Syndrome
Patients with this syndrome develop gastrinomas that drive the secretion of large amounts of acid. This can lead to severe gastroduodenal ulceration and other consequences of the uncontrolled hyperchlorhydria. Proton pump inhibitors are clearly the drugs of choice and are usually given at twice the dosage for routine ulcers, with the goal of therapy being to reduce acid secretion in the range of 1 to 10 mmol/hour.
Laxatives
Laxatives promote and facilitate bowel evacuation by acting locally to stimulate intestinal peristalsis, to soften bowel contents, or both.
1. Bulk laxatives. Distention of the intestinal wall by bowel contents stimulates propulsive movements of the gut musculature (peristalsis). Activation of intramural mechanoreceptors induces a neurally mediated ascending reflex contraction (red in A) and descending relaxation (blue) whereby the intraluminal bolus is moved in the anal direction.
Hydrophilic colloids or bulk gels (B) comprise insoluble and nonabsorbable carbohydrate substances that expand on taking up water in the bowel. Vegetable fibers in the diet act in this manner. They consist of the indigestible plant cell walls containing homoglycans that are resistant to digestive enzymes, e.g., cellulose (1_4β-linked glucose molecules vs. 1_4α glucoside bond in starch). Bran, a grain milling waste product, and linseed (flaxseed) are both rich in cellulose. Other hydrophilic colloids derive from the seeds of Plantago species or karaya gum. Ingestion of hydrophilic gels for the prophylaxis of constipation usually entails a low risk of side effects. However, with low fluid intake in combination with a pathological bowel
stenosis, mucilaginous viscous material could cause bowel occlusion (ileus).
Osmotically active laxatives (C) are soluble but nonabsorbable particles that retain water in the bowel by virtue of their osmotic action. The osmotic pressure (particle concentration) of bowel contents always corresponds to that of the extracellular space. The intestinal mucosa is unable to maintain a higher or lower osmotic pressure of the luminal contents. Therefore, absorption of molecules (e.g., glucose, NaCl) occurs isoosmotically, i.e., solute molecules are followed by a corresponding amount of water.
Conversely, water remains in the bowel when molecules cannot be absorbed. With Epsom and Glauber’s salts (MgSO4 and Na2SO4, respectively), the SO4 2– anion is nonabsorbable and retains cations to maintain electroneutrality. Mg2+ ions are also believed to promote release from the duodenal mucosa of cholecystokinin/pancreozymin, a polypeptide that also stimulates peristalsis. These so-called saline cathartics elicit a watery bowel discharge 1–3 h after administration (preferably in isotonic solution). They are used to purge the bowel (e.g., before bowel surgery) or to hasten the elimination of ingested poisons. Glauber’s salt (high Na+ content) is contraindicated in hypertension, congestive eart failure, and edema. Epsom salt is contraindicated in renal failure (risk of Mg2+ intoxication).
Osmotic laxative effects are also produced by the polyhydric alcohols,mannitol and sorbitol, which unlike glucose cannot be transported through the intestinal mucosa, as well as by the nonhydrolyzable disaccharide, lactulose. Fermentation of lactulose by colon bacteria results in acidification of bowel contents and microfloral damage. Lactulose is used in hepatic failure in order to prevent bacterial production of ammonia and its subsequent absorption (absorbable NH3 _ nonabsorbable NH4 +), so as to forestall hepatic coma.
2. Irritant laxatives—purgatives cathartics. Laxatives in this group exert an irritant action on the enteric mucosa (A). Consequently, less fluid is absorbed han is secreted. The increased filling of the bowel promotes peristalsis; excitation of sensory nerve endings elicits enteral hypermotility. According to the site of irritation, one distinguishes the small bowel irritant castor oil from the large bowel irritants anthraquinone and diphenolmethane derivatives.
Misuse of laxatives. It is a widely held belief that at least one bowel movement per day is essential for health; yet three bowel evacuations per week are quite normal. The desire for frequent bowel emptying probably stems from the time-honored, albeit
mistaken, notion that absorption of colon contents is harmful. Thus, purging has long been part of standard therapeutic practice. Nowadays, it is known that intoxication from intestinal substances is impossible as long as the liver functions normally. Nonetheless, purgatives continue to be sold as remedies to “cleanse the blood” or to rid the body of “corrupt humors.” There can be no objection to the ingestion of bulk substances for the purpose of supplementing low-residue “modern diets.” However, use of irritant purgatives or cathartics is not without hazards. Specifically, there is a risk of laxative dependence, i.e., the inability to do without them. Chronic intake of irritant purgatives disrupts the water and electrolyte balance of the body and can thus cause symptoms of illness (e.g., cardiac arrhythmias secondary to hypokalemia).
Causes of purgative dependence (B). The defecation reflex is triggered when the sigmoid colon and rectum are filled. A natural defecation empties the large bowel up to and including the descending colon. The interval betweeatural stool evacuations depends on the speed with which these colon segments are refilled. A large bowel irritant purgative clears out the entire colon. Accordingly, a longer period is needed until the next natural defecation can occur.
Fearing constipation, the user becomes impatient and again resorts to the laxative, which then produces the desired effect as a result of emptying out the upper colonic segments. Therefore, a “compensatory pause” following cessation of laxative use must not give cause for concern (1).In the colon, semifluid material entering from the small bowel is thickened by absorption of water and salts (from about 1000 to 150 mL/d). If, due to the action of an irritant purgative, the colon empties prematurely, an enteral loss of NaCl, KCl and water will be incurred. To forestall depletion of NaCl and water, the body responds with an increased release of aldosterone, which stimulates their reabsorption in the kidney.
Chologenic diarrhea results when bile acids fail to be absorbed in the ileum (e.g., after ileal resection) and enter the colon, where they cause enhanced secretion of electrolytes and water, leading to the discharge of fluid stools.
2.a Small Bowel Irritant Purgative, Ricinoleic Acid
Castor oil comes from Ricinus communis (castor plants; Fig: sprig, panicle, seed); it is obtained from the first coldpressing of the seed (shown iatural size). Oral administration of 10–30 mL of castor oil is followed within 0.5 to 3 h by discharge of a watery stool. Ricinoleic acid, but not the oil itself, is active. It arises as a result of the regular processes involved in fat digestion: the duodenal mucosa releases the enterohormone cholecystokinin/pancreozymin into the blood. The hormone elicits contraction of the gallbladder and discharge of bile acids via the bile duct, as well as release of lipase from the pancreas (intestinal peristalsis is also stimulated). Because of its massive effect, castor oil is hardly suitable for the treatment of ordinary constipation. It can be employed after oral ingestion of a toxin in order to hasten elimination and to reduce absorption of toxin from the gut. Castor oil is not indicated after the ingestion of lipophilic toxins likely to depend on bile acids for their absorption.
2.b Large Bowel Irritant Purgatives
Anthraquinone derivatives are of plant origin. They occur in the leaves (folia sennae) or fruits (fructus sennae) of the senna plant, the bark of Rhamnus frangulae and Rh. purshiana, (cortex frangulae, cascara sagrada), the roots of rhubarb (rhizoma rhei), or the leaf extract from Aloe species. The structural features of anthraquinone derivatives are illustrated by the prototype structure. Among other substituents, the anthraquinone nucleus contains hydroxyl groups, one of which is bound to a sugar (glucose, rhamnose). Following ingestion of galenical preparations or of the anthraquinone glycosides, discharge of soft stool occurs after a latency of 6 to 8 h. The anthraquinone glycosides themselves are inactive but are converted by colon bacteria to the active free aglycones.
Diphenolmethane derivatives were developed from phenolphthalein, an accidentally discovered laxative, use of which had beeoted to result in rare but severe allergic reactions. Bisacodyl and sodium picosulfate are converted by gut bacteria into the active colonirritant principle. Given by the enteral route, bisacodyl is subject to hydrolysis of acetyl residues, absorption, conjugation in liver to glucuronic acid (or also to sulfate), and biliary secretion into the duodenum. Oral administration is followed after approx. 6 to 8 h by discharge of soft formed stool. When given by suppository, bisacodyl produces its effect within 1 h.
Indications for colon-irritant purgatives are the prevention of straining at stool following surgery, myocardial infarction, or stroke; and provision of relief in painful diseases of the anus, e.g., fissure, hemorrhoids. Purgatives must not be given in abdominal complaints of unclear origin.
3. Lubricant laxatives. Liquid paraffin (paraffinum subliquidum) is almost nonabsorbable and makes feces softer and more easily passed. It interferes with the absorption of fat-soluble vitamins by trapping them. The few absorbed paraffin particles may induce formation of foreign-body granulomas in enteric lymph nodes (paraffinomas). Aspiration into the bronchial tract can result in lipoid pneumonia. Because of these adverse effects, its use is not advisable.
Antidiarrheal Agents
Causes of diarrhea (in red): Many bacteria (e.g., Vibrio cholerae) secrete toxins that inhibit the ability of mucosal enterocytes to absorb NaCl and water and, at the same time, stimulate mucosal secretory activity.
Bacteria or viruses that invade the gut wall cause inflammation characterized by increased fluid secretion into the lumen. The enteric
musculature reacts with increased peristalsis. The aims of antidiarrheal therapy are to prevent: (1) dehydration and electrolyte depletion; and (2) excessively high stool frequency. Different therapeutic approaches (in green) listed are variously suited for these purposes.
Adsorbent powders are nonabsorbable materials with a large surface area. These bind diverse substances, including toxins, permitting them to be inactivated and eliminated. Medicinal charcoal possesses a particularly large surface because of the preserved cell structures. The recommended effective antidiarrheal dose is in the range of 4–8 g. Other adsorbents are kaolin (hydrated aluminum silicate) and chalk.
Oral rehydration solution (g/L of boiled water: NaCl 3.5, glucose 20, NaHCO3 2.5, KCl 1.5). Oral administration of glucose-containing salt solutions enables fluids to be absorbed because toxins do not impair the cotransport of Na+ and glucose (as well as of H2O) through the mucosal epithelium. In this manner, although frequent discharge of stool is not prevented, dehydration is successfully corrected.
Opioids. Activation of opioid receptors in the enteric nerve plexus resultsin inhibition of propulsive motor activity and enhancement of segmentation activity. This antidiarrheal effect was formerly induced by application of opium tincture (paregoric) containing morphine. Because of the CNS effects (sedation, respiratory depression, physical dependence), derivatives with peripheral actions have been developed. Whereas diphenoxylate can still produce clear CNS effects, loperamide does not affect brain functions at normal dosage. Loperamide is, therefore, the opioid antidiarrheal of first choice. The prolonged contact time of intestinal contents and mucosa may also improve absorption of fluid. With overdosage, there is a hazard of ileus. It is contraindicated in infants below age 2 y.
Antibacterial drugs. Use of these agents (e.g., cotrimoxazole) is only rational when bacteria are the cause of diarrhea. This is rarely the case. It should be kept in mind that antibiotics also damage the intestinal flora which, in turn, can give rise to diarrhea.
Astringents such as tannic acid (home remedy: black tea) or metal salts precipitate surface proteins and are thought to help seal the mucosal epithelium. Protein denaturation must not include cellular proteins, for this would mean cell death. Although astringents induce constipation, a therapeutic effect in diarrhea is doubtful.
Demulcents, e.g., pectin (home remedy: grated apples) are carbohydrates that expand on absorbing water. They improve the consistency of bowel contents; beyond that they are devoid of any favorable effect.
Drugs for Dissolving Gallstones (A) Following its secretion from liver into bile, water-insoluble cholesterol is held in solution in the form of micellar complexes with bile acids and phospholipids. When more cholesterol is secreted than can be emulsified, it precipitates and forms gallstones (cholelithiasis). Precipitated cholesterol can be reincorporated into micelles, provided the cholesterol concentration in bile is below saturation.
Thus, cholesterol-containing stones can be dissolved slowly. This effect can be achieved by long-term oral administration of chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA). Both are physiologically occurring, stereoisomeric bile acids (position of the 7-hydroxy group being β in UCDA and α in CDCA). Normally, they represent a small proportion of the total amount of bile acid present in the body (circle diagram in A); however, this increases considerably with chronic administration because of enterohepatic cycling. Bile acids undergo almost complete reabsorption in the ileum. Small losses via the feces are made up by de novo synthesis in the liver, keeping the total amount of bile acids constant (3–5 g). Exogenous supply removes the need for de novo synthesis of bile acids. The particular acid being supplied gains an increasingly larger share of the total store. The altered composition of bile increases the capacity for cholesterol uptake. Thus, gallstones can be dissolved in the course of a 1- to 2 y treatment, provided that cholesterol stones are pure and not too large (<
Choleretics are supposed to stimulate production and secretion of dilute bile fluid. This principle has little therapeutic significance.
Cholekinetics stimulate the gallbladder to contract and empty, e.g., egg yolk, the osmotic laxative MgSO4, the cholecystokinin-related ceruletide (given parenterally). Cholekinetics are employed to test gallbladder function for diagnostic purposes.
Pancreatic enzymes (B) from slaughtered animals are used to relieve excretory insufficiency of the pancreas (disrupted digestion of fats; steatorrhea, inter alia). Normally, secretion of pancreatic enzymes is activated by cholecystokinin/pancreozymin, the enterohormone that is released into blood from the duodenal mucosa upon contact with chyme. With oral administration of pancreatic enzymes, allowance must be made for their partial inactivation by gastric acid (the lipases, particularly). Therefore, they are administered in acid-resistant dosage forms.
Antiflatulents (carminatives) serve to alleviate meteorism (excessive accumulation
of gas in the gastrointestinal tract). Aborad propulsion of intestinal contents is impeded when the latter are mixed with gas bubbles. Defoaming agents, such as dimethicone (dimethylpolysiloxane) and simethicone, in combination with charcoal, are given orally to promote separation of gaseous and semisolid contents. Antiflatulent plants – Fructus Carvi, Fructus foeniculi, Herba Origani.
• Carum carvi L.
Foeniculim vulgare Mill.
PEPTIC ULCER DISEASE
Peptic ulcer disease is characterized by ulcer formation in the esophagus, stomach, or duodenum, areas of the gastrointestinal (GI) mucosa that are exposed to gastric acid and pepsin. Gastric and duodenal ulcers are more common then esophageal ulcers. Peptic ulcers are attributed to an imbalance between cell-destructive and cell-protective effects (ie, increased destructive mechanisms or decreased protective mechanisms).
Cell-destructive effects include those of gastric acid (hydrochloric acid), pepsin, Helicobacter pylori (H. pylori) infection, and ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs). Gastric acid, a strong acid that can digest the stomach wall, is secreted by parietal cells in the mucosa of the stomach antrum, near the pylorus. The parietal cells contain receptors for acetylcholine, gastrin, and histamine, substances that stimulate gastric acid production. Acetylcholine is released by vagus nerve endings in response to stimuli, such as thinking about or ingesting food. Gastrin is a hormone released by cells in the stomach and duodenum in response to food ingestion and stretching of the stomach wall. It is secreted into the bloodstream and eventually circulated to the parietal cells.
Histamine is released from cells in the gastric mucosa and diffuses into nearby parietal cells. An enzyme system (hydrogen–potassium adenosine triphosphatase, or H, K-ATPase) catalyzes the production of gastric acid and acts as a gastric acid (proton) pump to move gastric acid from parietal cells in the mucosal lining of the stomach into the stomach lumen.
Pepsin is a proteolytic enzyme that helps digest protein foods and also can digest the stomach wall. Pepsin is derived from a precursor called pepsinogen, which is secreted by chief cells in the gastric mucosa. Pepsinogen is converted to pepsin only in a highly acidic environment (ie, when the pH of gastric juices is 3 or less).
H. pylori is a gram-negative bacterium found in the gastric mucosa of most clients with chronic gastritis, about 75% of clients with gastric ulcers, and more than 90% of clients with duodenal ulcers. It is spread mainly by the fecal-oral route. However, iatrogenic spread by contaminated endoscopes, biopsy forceps, and nasogastric tubes has also occurred. Once in the body, the organism colonizes the mucus-secreting epithelial cells of the stomach mucosa and is thought to produce gastritis and ulceration by impairing mucosal function. Eradication of the organism accelerates ulcer healing and significantly
decreases the rate of ulcer recurrence.
Cell-protective effects (eg, secretion of mucus and bicarbonate, dilution of gastric acid by food and secretions, prevention of diffusion of hydrochloric acid from the stomach lumen back into the gastric mucosal lining, the presence of prostaglandin E, alkalinization of gastric secretions by pancreatic juices and bile, and perhaps other mechanisms) normally prevent autodigestion of stomach and duodenal tissues and ulcer formation. A gastric or duodenal ulcer may penetrate only the mucosal surface or it may extend into the smooth muscle layers. When superficial lesions heal, no defects remain. When smooth muscle heals, however, scar tissue remains and the mucosa that regenerates to cover the scarred muscle tissue may be defective.
These defects contribute to repeated episodes of ulceration. Although there is considerable overlap in etiology, clinical manifestations, and treatment of gastric and duodenal ulcers, there are differences as well. Gastric ulcers (which may be preceded by less severe mucosal defects such as erosions or gastritis) are often associated with stress (eg, major trauma or severe medical illness), NSAID ingestion, or H. pylori infection of the stomach. They are often manifested by painless bleeding and take longer to heal than duodenal ulcers. Gastric ulcers associated with stress may occur in any age group and are usually acute iature; those associated with H. pylori infection or NSAID ingestion are more likely to occur in older adults, especially in the sixth and seventh decades, and
to be chronic iature. Duodenal ulcers are strongly associ ated with H. pylori infection and NSAID ingestion, may occur at any age, occur about equally in men and women, are often manifested by abdominal pain, and are usually chronic iature. They are also associated with cigarette smoking. Compared with nonsmokers, smokers are more likely to develop duodenal ulcers, their ulcers heal more slowly with treatment, and the ulcers recur more rapidly.
Gastroesophageal Reflux Disease (GERD)
GERD, the most common disorder of the esophagus, is characterized by regurgitation of gastric contents into the esophagus and exposure of esophageal mucosa to gastric acid and pepsin. The same amount of acid–pepsin exposure may lead to different amounts of mucosal damage, possibly related to individual variations in esophageal mucosal resistance. Acid reflux often occurs after the evening meal and decreases during sleep. The main symptom is heartburn (pyrosis), which increases with a recumbent position or bending over. Effortless regurgitation of acidic fluid into the mouth, especially after a meal and at night, is often indicative of GERD. Depending on the frequency and extent of acid–pepsin reflux, GERD may result in mild to severe esophagitis or esophageal ulceration. Pain on swallowing usually means erosive or ulcerative esophagitis.
The main cause of GERD is thought to be an incompetent lower esophageal sphincter (LES). Normally, the LES is contracted or closed and prevents the reflux of gastric contents. It opens or relaxes on swallowing, to allow passage of food or fluid, then contracts again. Several circumstances contribute to impaired contraction of the LES and the resulting reflux, including foods (eg, fats, chocolate), fluids (alcohol, caffeinated beverages), medications (eg, beta adrenergics, calcium channel blockers, nitrates), gastric distention, cigarette smoking, and recumbent posture. GERD occurs in men, women, and children, but is especially common during pregnancy and after 40 years of age.
TYPES OF DRUGS
Drugs used in the treatment of acid-peptic disorders promote healing of lesions and prevent recurrence of lesions by decreasing cell-destructive effects or increasing cell-protective effects. Several types of drugs are used, alone and in various combinations. Antacids neutralize gastric acid and decrease pepsin production; antimicrobials and bismuth can eliminate H. pylori infection; histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) decrease gastric acid secretion; sucralfate provides a barrier between mucosal erosions or ulcers and gastric secretions; and misoprostol restores prostaglandin activity. Types of drugs and individual agents are described in the following sections; dosages are listed in Drugs at a Glance: Representative Antacid Products and Drugs at a Glance: Drugs for Acid-Peptic Disorders.
Antacids
Antacids are alkaline substances that neutralize acids. They react with hydrochloric acid in the stomach to produce neutral, less acidic, or poorly absorbed salts and to raise the pH (alkalinity) of gastric secretions. Raising the pH to approximately 3.5 neutralizes more than 90% of gastric acid and inhibits conversion of pepsinogen to pepsin. Commonly used antacids are aluminum, magnesium, and calcium compounds. Antacids differ in the amounts needed to neutralize gastric acid (50 to 80 mEq of acid is produced hourly), in onset of action, and in adverse effects. Aluminum compounds have a low neutralizing capacity (ie, relatively large doses are required) and a slow onset of action. They can cause constipation. In people who ingest large amounts of aluminum-based antacids over a long period, hypophosphatemia and osteomalacia may develop because aluminum combines with phosphates in the GI tract and prevents phosphate absorption. Aluminum compounds are rarely used alone for acid-peptic disorders.
Magnesium-based antacids have a high neutralizing capacity and a rapid onset of action. They may cause diarrhea and hypermagnesemia.
Calcium compounds have a rapid onset of action but may cause hypercalcemia and hypersecretion of gastric acid (“acid rebound”) due to stimulation of gastrin release, if large doses are used. Consequently, calcium compounds are rarely used in peptic ulcer disease. Commonly used antacids are mixtures of aluminum hydroxide and magnesium hydroxide (eg, Gelusil, Mylanta, Maalox).
Some antacid mixtures contain other ingredients, such as simethicone or alginic acid. Simethicone is an antiflatulent drug available alone as Mylicon. When added to antacids, simethicone does not affect gastric acidity. It reportedly decreases gas bubbles, thereby reducing GI distention and abdominal discomfort. Alginic acid (eg, in Gaviscon) produces a foamy, viscous layer on top of gastric acid and thereby decreases backflow of gastric acid onto esophageal mucosa while the person is in an upright position.
Antacids act primarily in the stomach and are used to prevent or treat peptic ulcer disease, GERD, esophagitis, heartburn, gastritis, GI bleeding, and stress ulcers. Aluminum-based antacids also are given to clients with chronic renal failure and hyperphosphatemia to decrease absorption of phosphates in food. Magnesium-based antacids are contraindicated in clients with renal failure.
Helicobacter pylori Agents
Multiple drugs are required to eradicate H. pylori organisms and heal related ulcers. Effective combinations include two antimicrobials and a PPI or an H2RA. For the antimicrobial component, two of the following drugs—amoxicillin, clarithromycin, metronidazole, or tetracycline—are used.
A single antimicrobial agent is not used because of concern about emergence of drug-resistant H. pylori organisms. For clients with an active ulcer, adding an antisecretory drug (ie, H2RA or PPI) to an antimicrobial regimen accelerates symptom relief and ulcer healing. In addition, antimicrobial – antisecretory combinations are associated with low ulcer recurrence rates. A bismuth preparation is added to some regimens.
Bismuth exerts antibacterial effects against H. pylori by disrupting bacterial cell walls, preventing the organism from adhering to gastric epithelium, and inhibiting bacterial enzymatic and proteolytic activity. It also increases secretion of mucus and bicarbonate, inhibits pepsin activity, and accumulates in ulcer craters. Although several regimens are effective in H. pylori infection, three-drug regimens with a PPI and two antibacterial drugs may be preferred. The regimen using metronidazole, a bismuth compound, tetracycline, and an antisecretory drug is very effective in healing ulcers. However, this regimen is not well tolerated, partly because of the multiple daily doses required. Because client compliance is a difficulty with all the H. pylori eradication regimens, some drug combinations are packaged as individual doses to increase convenience. For example, Helidac contains bismuth, metronidazole, and tetracycline (taken with an H2RA); Prevpac contains amoxicillin, clarithromycin, and lansoprazole.
Histamine-2 Receptor Antagonists (H2RAs)
Histamine is a substance found in almost every body tissue and released in response to certain stimuli (eg, allergic reactions, tissue injury). Once released, histamine causes contraction of smooth muscle in the bronchi, GI tract, and uterus; dilation and increased permeability of capillaries; dilation of cerebral blood vessels; and stimulation of sensory nerve endings to produce pain and itching.
Histamine also causes strong stimulation of gastric acid secretion. Vagal stimulation causes release of histamine from cells in the gastric mucosa. The histamine then acts on receptors located on the parietal cells to increase production of hydrochloric acid. These receptors are called the H2 receptors. Traditional antihistamines or H1 receptor antagonists prevent or reduce other effects of histamine but do not block histamine effects on gastric acid production. The H2RAs inhibit both basal secretion of gastric acid and the secretion stimulated by histamine, acetylcholine, and gastrin. They decrease the amount, acidity, and pepsin content of gastric juices. A single dose of an H2RA can inhibit acid secretion for 6 to 12 hours and a continuous intravenous (IV) infusion can inhibit secretion for prolonged periods.
Clinical indications for use include prevention and treatment of peptic ulcer disease, gastroesophageal reflux disease, esophagitis, GI bleeding due to acute stress ulcers, and Zollinger-Ellison syndrome. With gastric or duodenal ulcers, healing occurs within 6 to 8 weeks; with esophagitis, healing occurs in about 12 weeks.
Over-the-counter oral preparations, at lower dosage strengths, are approved for the treatment of heartburn. There are no known contraindications, but the drugs should be used with caution in children, pregnant women, older adults, and clients with impaired renal or hepatic function. Dosage should be reduced in the presence of impaired renal function.
Adverse effects occur infrequently with usual doses and duration of treatment. They are more likely to occur with prolonged use of high doses and in older adults or those with impaired renal or hepatic function.
Cimetidine, ranitidine, famotidine, and nizatidine are the four available H2RAs. Cimetidine was the first, and it is still widely used. It is well absorbed after oral administration. After a single dose, peak blood level is reached in 1 to 1.5 hours, and an effective concentration is maintained about 6 hours. The drug is distributed in almost all body tissues.
Cimetidine should be used with caution during pregnancy because it crosses the placenta, and it should not be taken during lactation because it is excreted in breast milk. Most of an oral dose is excreted unchanged in the urine within 24 hours; some is excreted in bile and eliminated in feces.
For acutely ill clients, cimetidine is given intravenously. A major disadvantage of cimetidine is that it inhibits the hepatic metabolism of numerous other drugs, thereby increasing blood levels and risks of toxicity with the inhibited drug.
Ranitidine is more potent than cimetidine on a weight basis, and smaller doses can be given less frequently. In addition, ranitidine causes fewer drug interactions than cimetidine.
Oral ranitidine reaches peak blood levels 1 to 3 hours after administration, and is metabolized in the liver; approximately 30% is excreted unchanged in the urine.
Parenteral ranitidine reaches peak blood levels in about 15 minutes; 65% to 80% is excreted unchanged in the urine.
Famotidine and nizatidine are similar to cimetidine and ranitidine. Compared with cimetidine, the other drugs cause similar effects except they are less likely to cause mental confusion and gynecomastia (antiandrogenic effects). In addition, they do not affect the cytochrome P450 drug-metabolizing system in the liver and therefore do not interfere with the metabolism of other drugs.
Proton Pump Inhibitors
PPIs are strong inhibitors of gastric acid secretion. These drugs bind irreversibly to the gastric proton pump (ie, the enzyme H, K-ATPase) to prevent the “pumping” or release of gastric acid from parietal cells into the stomach lumen and therefore block the final step of acid production. Inhibition of the proton pump suppresses gastric acid secretion in response to all primary stimuli, histamine, gastrin, and acetylcholine.
Thus, the drugs inhibit both daytime (including meal-stimulated) and nocturnal (unstimulated) acid secretion.
Indications for use include treatment of peptic ulcer disease, erosive gastritis, GERD, and Zollinger-Ellison syndrome. PPIs are usually the drugs of choice for treatment of duodenal and gastric ulcers, GERD with erosive esophagitis, and Zollinger-Ellison syndrome. Compared with H2RAs, PPIs suppress gastric acid more strongly and for a longer time. This effect provides faster symptom relief and faster healing in acidrelated diseases. For example, healing of duodenal and gastric ulcers after 2 weeks is similar to the healing after 4 weeks of H2RA therapy. The PPIs and H2RAs are similarly effective in maintenance therapy of peptic ulcer disorders, with similar rates of ulcer recurrence. In clients with GERD, PPIs usually abolish symptoms within 1 to 2 weeks and heal esophagitis within 8 weeks. The drugs are also effective in maintenance therapy to prevent recurrence of esophagitis. In clients with H. pylori–associated ulcers, eradication of the organism with antimicrobial drugs is preferable to long-term maintenance therapy with antisecretory drugs.
The drugs usually are well tolerated; adverse effects are minimal with both short- and long-term use. Nausea, diarrhea, and headache are the most frequently reported adverse effects. However, long-term consequences of profound gastric acid suppression are unknown.
Omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole are available PPIs.
Omeprazole was the first and is still widely used. It is well absorbed after oral administration, highly bound to plasma proteins (about 95%), metabolized in the liver, and excreted in the urine (about 75%) and bile or feces.
Acid-inhibiting effects occur within 2 hours and last 72 hours or longer. When the drug is discontinued, effects persist for 48 to 72 hours or longer, until the gastric parietal cells can synthesize additional H, K-ATPase.
The other drugs are very similar to omeprazole. Omeprazole (Prilosec) is expected to be approved for over-the-counter sales for treating heartburn. If heartburn is not improved within 14 days of treatment, clients should be evaluated by their health care provider. Prescription omeprazole has been very expensive; with nonprescription use, the cost should be much less.
Prostaglandin
Naturally occurring prostaglandin E, which is produced in mucosal cells of the stomach and duodenum, inhibits gastric acid secretion and increases mucus and bicarbonate secretion, mucosal blood flow, and perhaps mucosal repair. It also inhibits the mucosal damage produced by gastric acid, aspirin, and NSAIDs. When synthesis of prostaglandin E is inhibited, erosion and ulceration of gastric mucosa may occur. This is the mechanism by which aspirin and other NSAIDs are thought to cause gastric and duodenal ulcers.
Misoprostol is a synthetic form of prostaglandin E approved for concurrent use with NSAIDs to protect gastric mucosa from NSAID-induced erosion and ulceration.
It is indicated for clients at high risk of GI ulceration and bleeding, such as those taking high doses of NSAIDs for arthritis and older adults. It is contraindicated in women of childbearing potential, unless effective contraceptive methods are being used, and during pregnancy, because it may induce abortion. The most common adverse effects are diarrhea (occurs in 10% to 40% of recipients) and abdominal cramping. Older adults may be unable to tolerate misoprostol-induced diarrhea and abdominal discomfort.
Sucralfate
Sucralfate is a preparation of sulfated sucrose and aluminum hydroxide that binds to normal and ulcerated mucosa.
It is used to prevent and treat peptic ulcer disease. It is effective even though it does not inhibit secretion of gastric acid or pepsin and it has little neutralizing effect on gastric acid. Its mechanism of action is unclear, but it is thought to act locally on the gastric and duodenal mucosa. Possible mechanisms include binding to the ulcer and forming a protective barrier between the mucosa and gastric acid, pepsin, and bile salts; neutralizing pepsin; stimulating prostaglandin synthesis in the mucosa; and exerting healing effects through the aluminum component. Sucralfate is effective in healing duodenal ulcers and in maintenance therapy to prevent ulcer recurrence. In general, the rates of ulcer healing with sucralfate are similar to the rates with H2RAs.
Adverse effects are low in incidence and severity because sucralfate is not absorbed systemically. Constipation and dry mouth are most often reported. The main disadvantages of using sucralfate are that the tablet is large; it must be given at least twice daily; it requires an acid pH for activation and should not be given with an antacid, H2RA, or PPI; and it may bind other drugs and prevent their absorption. In general, sucralfate should be given 2 hours before or after other drugs.
Herbal and Dietary Supplements
Several herbal supplements are promoted as aiding heartburn, gastritis, and peptic ulcer disease. Most have not been studied in humans and there is little, if any, evidence that they are either safe or effective for the proposed uses. Given the known safety and effectiveness of available drugs and the possible consequences of delaying effective treatment, the use of herbal supplements for any acid-peptic disorder should be discouraged.
PRINCIPLES OF THERAPY
Drug Selection
All of the drugs used for acid-peptic disorders are effective for indicated uses; the choice of drugs may depend on etiology, acuity, severity of symptoms, cost, and convenience.
General guidelines include the following: • Proton pump inhibitors are the drugs of first choice in most situations. They heal gastric and duodenal ulcers more rapidly and may be more effective in erosive esophagitis, erosive gastritis, and Zollinger-Ellison syndrome than H2RAs.
They are also effective in eradicating H. pylori infection when combined with two antibacterial drugs. Most PPIs are given orally only; pantoprazole (Protonix IV) is a parenteral formulation. PPIs are more expensive than H2RAs.
• H. pylori infection should be considered in most cases of peptic ulcer disease. If infection is confirmed by appropriate diagnostic tests, agents to eradicate the organisms should be drugs of first choice. The most recommended drug regimen is a combination of a PPI and two antibacterial drugs.
• H2RAs have been replaced as first-choice drugs by the PPIs for most indications, but are still widely used. Cimetidine may be less expensive but it may cause confusion and antiandrogenic effects. It also increases the risks of toxicity with several commonly used drugs. Compared with cimetidine, other H2RAs are more potent on a weight basis and have a longer duration of action, so they can be given in smaller, less frequent doses. In addition, they do not alter the hepatic metabolism of other drugs. Over-the-counter H2RAs are indicated for the treatment of heartburn. In some cases, clients may depend on self-medication with over-the-counter drugs and delay seeking treatment for peptic ulcer disease or GERD. For prescription or nonprescription uses, cimetidine is preferably taken by clients who are taking no other medications.
• Antacids are often used as needed to relieve heartburn and abdominal discomfort. If used to treat acid-peptic disorders, they are more often used with other agents than alone and require a regular dosing schedule. The choice of antacid should be individualized to find a preparation that is acceptable to the client in terms of taste, dosage, and convenience of administration. Some guidelines include the following:
1. Most commonly used antacids combine aluminum hydroxide and magnesium hydroxide. The combination decreases the adverse effects of diarrhea (with magnesium products) and constipation (with aluminum products). Calcium carbonate is effective in relieving heartburn, but it is infrequently used to treat peptic ulcers or GERD.
2. Antacids may be used more ofteow that low doses (eg, 2 antacid tablets 4 times a day) have been shown to be effective in healing gastric and duodenal ulcers. All of the low-dose regimens contained aluminum, and the aluminum rather than acid neutralization may be the important therapeutic factor.
Compared with other drugs for acid-peptic disorders, low-dose antacids are inexpensive and cause few adverse effects. In addition, tablets are as effective as liquids and usually more convenient to use.
3. Antacids with magnesium are contraindicated in renal disease because hypermagnesemia may result; those with high sugar content are contraindicated in diabetes mellitus.
4. Additional ingredients may be helpful to some clients. Simethicone has no effect on intragastric pH but may be useful in relieving flatulence or gastroesophageal reflux. Alginic acid may be useful in clients with daytime acid reflux and heartburn.
• Sucralfate must be taken before meals, and this is inconvenient for some clients.
Guidelines for Therapy With Proton Pump Inhibitors
1. Recommended doses of PPIs heal most gastric and duodenal ulcers in about 4 weeks. Large gastric ulcers may require 8 weeks.
2. The drugs may be used to maintain healing of gastric and duodenal ulcers and decrease risks of ulcer recurrence.
3. A PPI and two antimicrobial drugs is the most effective regimens for eradication of H. pylori organisms.
4. With GERD, higher doses or longer therapy may be needed for severe disease and esophagitis. Lower doses can maintain symptom relief and esophageal healing. ease, helping the client follow the prescribed therapeutic regimen helps to promote healing and prevent complications.
• Diet therapy is of minor importance in prevention or treatment of peptic ulcer disease. Some physicians prescribe no dietary restrictions, whereas others suggest avoiding or minimizing highly spiced foods, gas-forming foods, and caffeine-containing beverages.
• With heartburn and esophagitis, helpful measures are those that prevent or decrease gastroesophageal reflux of gastric contents (eg, avoiding irritant, highly spiced, or fatty foods; eating small meals; not lying down for 1 to 2 hours after eating; elevating the head of the bed; and avoiding obesity, constipation, or other conditions that increase intra-abdominal pressure).
Evaluation
• Observe and interview regarding drug use.
• Observe and interview regarding relief of symptoms.
• Observe for signs and symptoms of complications.
• Observe and interview regarding adverse drug effects.
Guidelines for Therapy With Histamine-2 Receptor Antagonists
1. For an acute ulcer, full dosage may be given up to 8 weeks. When the ulcer heals, dosage may be reduced by 50% for maintenance therapy to prevent recurrence.
2. For duodenal ulcers, a single evening or bedtime dose produces the same healing effects as multiple doses. Commonly used nocturnal doses are cimetidine 800 mg, ranitidine 300 mg, nizatidine 300 mg, or famotidine 40 mg.
3. For gastric ulcers, the optimal H2RA dosage schedule has not been established. Gastric ulcers heal more slowly than duodenal ulcers and most authorities prescribe 6 to 8 weeks of drug therapy.
4. To maintain ulcer healing and prevent recurrence, long-term H2RA therapy is often used. The drug is usually given as a single bedtime dose, but the amount is reduced by 50% (ie, cimetidine 400 mg, ranitidine 150 mg, nizatidine 150 mg, or famotidine 20 mg).
5. For Zollinger-Ellison syndrome, high doses as often as every 4 hours may be required.
6. For severe reflux esophagitis, multiple daily doses may be required for adequate symptom control.
7. Dosage of all these drugs should be reduced in the presence of impaired renal function.
8. Antacids are often given concurrently with H2RAs to relieve pain. They should not be given at the same time (except for Pepcid Complete) because the antacid reduces absorption of the other drug. H2RAs usually relieve pain after 1 week of administration.
9. These drugs are available in a wide array of products and precautions must be taken to ensure the correct formulation, dosage strength, and method of administration for the intended use. For example, cimetidine is available in tablets of 100, 200, 300, 400, 800 mg, an oral liquid with 300 mg/5 mL, and injectable solutions. Ranitidine is available in tablets of 75, 150, and 300 mg, effervescent tablets of 150 mg, capsules (Zantac GELdose) of 150 and 300 mg, a liquid syrup with 15 mg/mL, effervescent granules of 150 mg, and injectable solutions of 1 mg/mL and 25 mg/mL. Nizatidine is available in tablets of 75 mg and capsules of 150 and 300 mg and famotidine in tablets of 10, 20, and 40 mg, chewable tablets of 10 mg, orally disintegrating tablets (Pepcid RPD) of 20 and 40 mg, a powder for oral suspension that contains 40 mg/5 mL when reconstituted, and injection solutions of 10 mg/mL and 20 mg/50 mL.
10. All of the drugs are available by prescription and overthe-counter (OTC). When prescriptions are given, clients should be advised to avoid concomitant use of OTC versions of the same or similar drugs.
Guidelines for Therapy With Sucralfate
1. When sucralfate is used to treat an ulcer, it should be administered for 4 to 8 weeks unless healing is confirmed by radiologic or endoscopic examination.
2. When used long term to prevent ulcer recurrence, dosage should be reduced.
Guidelines for Therapy With Antacids
1. To prevent stress ulcers in critically ill clients and to treat acute GI bleeding, nearly continuous neutralization of gastric acid is desirable. Dose and frequency of administration must be sufficient to neutralize approximately 50 to 80 mEq of gastric acid each hour. This can be accomplished by a continuous intragastric drip through a nasogastric tube or by hourly administration.
2. When a client has a nasogastric tube in place, antacid dosage may be titrated by aspirating stomach contents, determining pH, and then basing the dose on the pH. (Most gastric acid is neutralized and most pepsin activity is eliminated at a pH above 3.5.)
3. When prescribing antacids to treat active ulcers, it has long been recommended to take them 1 hour and 3 hours after meals and at bedtime for greater acid neutralization. This schedule is effective but inconvenient for many clients. More recently, lower doses taken less often have been found effective in healing duodenal or gastric ulcers even though less acid neutralization occurs.
4. It was formerly thought that liquid antacid preparations were more effective. Now, tablets are considered as effective as liquids.
5. When antacids are used to relieve pain, they usually may be taken as needed. However, they should not be taken in high doses or for prolonged periods because of potential adverse effects.
Effects of Acid Suppressant Drugs on Other Drugs
Antacids may prevent absorption of most drugs taken at the same time, including benzodiazepine antianxiety drugs, corticosteroids, digoxin, H2RAs (eg, cimetidine), iron supplements, phenothiazine antipsychotic drugs, phenytoin, fluoroquinolone antibacterials, and tetracyclines. Antacids increase absorption of a few drugs, including levodopa, quinidine, and valproic acid. These interactions can be avoided or minimized by separating
administration times by 1 to 2 hours.
H2RAs may alter the effects of several drugs. Most significant effects occur with cimetidine, which interferes with the metabolism of many commonly used drugs. Consequently, the affected drugs are eliminated more slowly, their serum levels are increased, and they are more likely to cause adverse effects and toxicity unless dosage is reduced. Interacting drugs include antidysrhythmics (lidocaine, propafenone, quinidine), the anticoagulant warfarin, anticonvulsants (carbamazepine, phenytoin), benzodiazepine antianxiety or hypnotic agents (alprazolam, diazepam, flurazepam, triazolam), beta-adrenergic blocking agents (labetalol, metoprolol, propranolol), the bronchodilator theophylline, calcium channel blocking agents (eg, verapamil), tricyclic antidepressants (eg, amitriptyline), and sulfonylurea antidiabetic drugs. In addition, cimetidine may increase serum levels (eg, fluorouracil, procainamide and its active metabolite) and pharmacologic effects of other drugs (eg, respiratory depression with opioid analgesics) by unidentified mechanisms.
Cimetidine also may decrease effects of several drugs, including drugs that require an acidic environment for absorption (eg, iron salts, indomethacin, fluconazole, tetracyclines) and miscellaneous drugs (eg, digoxin, tocainide) by unknown mechanisms.
Ranitidine, famotidine, and nizatidine do not inhibit the cytochrome P450 metabolizing enzymes. Ranitidine decreases absorption of diazepam if given at the same time and increases hypoglycemic effects of glipizide. Nizatidine increases serum salicylate levels in people taking high doses of aspirin.
PPIs have relatively few effects on other drugs. Omeprazole increases blood levels of some benzodiazepines (diazepam, flurazepam, triazolam), phenytoin, and warfarin, probably by inhibiting hepatic metabolism. These interactions have not been reported with the other PPIs.
Sucralfate decreases absorption of ciprofloxacin and other fluoroquinolones, digoxin, phenytoin, and warfarin. Sucralfate binds to these drugs when both are present in the GI tract. This interaction can be avoided or minimized by giving the interacting drug 2 hours before sucralfate.
Effects of Acid Suppressant Drugs on Nutrients
Dietary folate, iron, and vitamin B12 are better absorbed from an acidic environment. When gastric fluids are made less acidic by antacids, H2RAs, or PPIs, deficiencies of these nutrients may occur. In addition, sucralfate interferes with absorption of fat-soluble vitamins, and magnesium-containing antacids interfere with absorption of vitamin A.
Use in Children
Antacids may be given to ambulatory children in doses of 5 to 15 mL every 3 to 6 hours or after meals and at bedtime, as for adults with acid-peptic disorders. For prevention of GI bleeding in critically ill children, 2 to 5 mL may be given to infants and 5 to 15 mL to children every 1 to 2 hours. Safety and effectiveness of other antiulcer drugs have not been established for children.
Although PPIs are not approved by the Food and Drug Administration for use in children and are not available in pediatric dosage formulations, they are widely used in the treatment of peptic ulcer and gastroesophageal disease. They are also used to eradicate H. pylori organisms. Most published reports involve adult doses for children older than 3 years of age. Some clinicians titrate dosage by a child’s weight, such as an initial dose of 0.7 mg/kg/day.
Use in Older Adults
All of the antiulcer, anti-heartburn drugs may be used in older adults. With antacids, smaller doses may be effective because older adults usually secrete less gastric acid than younger adults. Further, with decreased renal function, older adults are more likely to have adverse effects, such as neuromuscular effects with magnesium-containing antacids. Many physicians recommend calcium carbonate antacids (eg, Tums) as a calcium supplement to prevent or treat osteoporosis in older women. With H2RAs, older adults are more likely to experience adverse effects, especially confusion, agitation, and disorientation with cimetidine. In addition, older adults often have decreased renal function, and doses need to be reduced.
Older adults often take large doses of NSAIDs for arthritis and therefore are at risk for development of acute gastric ulcers and GI bleeding. Thus, they may be candidates for treatment with misoprostol. Dosage of misoprostol may need to be reduced to prevent severe diarrhea and abdominal cramping.
PPIs and sucralfate are well tolerated by older adults. A PPI is probably the drug of choice for treating symptomatic GERD because evidence suggests that clients 60 years of age and older require stronger antisecretory effects than younger adults. No dosage reduction is recommended for older adults.
Use in Renal Impairment
A major concern with antacids is the use of magnesium containing preparations (eg, Mylanta, Maalox). These are contraindicated in clients with impaired renal function (creatinine clearance <30 mL/minute) because 5% to 10% of the magnesium may be absorbed and accumulate to cause hypermagnesemia. In addition, antacids with calcium carbonate can cause alkalosis and raise urine pH; chronic use may cause renal stones, hypercalcemia, and renal failure.
Antacids containing aluminum hydroxide (eg, Amphogel, Rolaids) are the antacids of choice in clients with chronic renal failure. Aluminum tends not to accumulate and it binds with phosphate in the GI tract to prevent phosphate absorption and hyperphosphatemia.
With PPIs, no special precautions or dosage reductions are required in clients with renal impairment.
All of the available H2RAs are eliminated through the kidneys, and dosage needs to be substantially reduced in clients with renal impairment to avoid adverse effects. Cimetidine may cause mental confusion in clients with renal impairment. It also blocks secretion of creatinine in renal tubules, thereby decreasing creatinine clearance and increasing serum creatinine level. With moderate to severe renal impairment, recommended dosages include cimetidine 300 mg every 12 hours, ranitidine 150 mg orally once daily or intravenously every 18 to 24 hours, and famotidine 20 mg at bedtime or every 36 to 48 hours if indicated. Dosage may be cautiously increased if necessary and if renal function is closely monitored. For clients on hemodialysis, an H2RA should be given at the end of dialysis.
Use in Hepatic Impairment
PPIs are metabolized in the liver and may cause transient elevations in liver function tests. With omeprazole, bioavailability is increased because of decreased first-pass metabolism, and plasma half-life is increased. However, dosage adjustments are not recommended. Lansoprazole and rabeprazole should be used cautiously and dosage should be reduced in clients with severe liver impairment.
H2RAs are partly metabolized in the liver and may be eliminated more slowly in clients with impaired liver function. A major concern with cimetidine is that it can inhibit hepatic metabolism of many other drugs.
Use in Critical Illness
Gastric acid suppressant drugs (eg, PPIs and H2RAs) and sucralfate, are commonly used in critically ill clients.
The PPIs are the strongest gastric acid suppressants and are usually well tolerated. For clients who cannot take drugs orally, pantoprazole can be given IV.
The H2RAs are used to prevent stress-induced gastric ulceration in adults and children. Except for renal impairment, in which dosage must be reduced, information about the pharmacokinetics of these drugs in critically ill clients is limited and only cimetidine and ranitidine have been studied. Compared with healthy people, critically ill clients had a longer half-life and lower clearance rate for H2RAs. The drugs are usually given by intermittent IV infusion.
Ranitidine or famotidine is preferred because critically ill clients often require numerous other drugs with which cimetidine may interact and alter effects. Nizatidine is not available in a parenteral formulation.
Home Care
All of the antiulcer, anti-heartburn drugs are commonly taken in the home setting, usually by self-administration. The home care nurse can assist clients by providing information about taking the drugs correctly and monitoring responses.
If cimetidine is being taken, the home care nurse needs to assess for potential drug–drug interactions. With OTC H2RAs, clients should be instructed to avoid daily use of maximum doses for longer than 2 weeks. If use of antacids or OTC H2RAs seems to be excessive or prolonged, the client should be assessed for peptic ulcer disease or GERD.
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