Gastrointestinal agents –1. (Tinctura Absithii, herbae Centaurii, insulinum, Peritolum, Phepraninum, Masindolum, Apomorphini hydrochloridum, radix Ipecacuanae, Cupri sulfas, Triftazinum, Aethaperazinum, “Aeronum”, Metoclopramidum, (Reglan, Cerucal), Aropini sulfas, Pentagastrinum, Pepsinum, Acidum hydrochloricum dilutum, Ranitidinum, Famotidinum, Pirensepinum, Omeprasolum, Natrii hydrocarbonas, Magnesii oxydum, Aluminii hydroxydum, Almagel, Sucralfat, Vismuti dinytras, Misoprostolum)
Gastrointestinal agents –2. (Pancretinum, Mesim forte, Festal, Creon, Contrycalum, Acidum aminocapronicum, “Allocholum, Cholenzymum, Acidum chenodeoxycholicum, Magnesii sulfas, Natrii sulfas, Tabulettae radicis Rhei, cortex Frangulae, folium Sennae, Gutalax, Bisacodilum, Caphyolum, Regulax)
Agents acting on the function of digestive organs
Agents acting on the function of digestive organs
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. Alkalization 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
Peptic ulcer
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 United States: cimetidine (TAGAMET), ranitidine (ZANTAC), famotidine (PEPCID), and nizatidine (AXID). Their different chemical structures do not alter the drugs’ clinical efficacies as much as they determine interactions with other drugs and change the side-effect profiles. H2RAs inhibit acid production by reversibly competing with histamine for binding to H2 receptors on the basolateral membrane of parietal cells.
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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Figure 6 |
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
Proton pump inhibitors have largely replaced H2 antagonists in the treatment of peptic ulcer disease.
Nocturnal acid suppression affords effective ulcer healing in the majority of patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime for acute, uncomplicated ulcers, resulting in ulcer healing rates greater than 80–90% after 6–8 weeks of therapy. For patients with acute peptic ulcers caused by H pylori, H2 antagonists no longer play a significant therapeutic role. For the minority of patients in whom H pylori cannot be successfully eradicated, H2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose in order to prevent ulcer recurrence (eg, ranitidine 150 mg, famotidine 20 mg). For patients with ulcers caused by aspirin or other NSAIDs, H2 antagonists provide rapid ulcer healing so long as the NSAID is discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given to promote ulcer healing.
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
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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Figure 8 |
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 theirsymptoms.
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.
Peptic Ulcer Disease
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)
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). 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 no absorbable 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.
The action of aldosterone is, however, associated with increased renal excretion of KCl. The enteral and renal K+ loss add up to a K+ depletion of the body, evidenced by a fall in serum K+ concentration (hypokalemia). This condition is accompanied by
a reduction in intestinal peristalsis (bowel atonia). The affected individual infers “constipation,” again partakes of the purgative, and the vicious circle is closed (2).
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 absorbedparaffin 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.
Preparations Available
Antacids
Aluminum hydroxide gel* (Amphojel, ALternaGEL, others)
Oral: 300, 500, 600 mg tablets; 400, 500 mg capsules; 320, 450, 675 mg/5 mL suspension
Calcium carbonate* (Tums, others)
Oral: 350, 420, 500, 600, 650, 750, 1000, 1250 mg chewable tablets; 1250 mg/5 mL suspension
Combination aluminum hydroxide and magnesium hydroxide preparations* (Maalox,
Mylanta, Gaviscon, Gelusil, others)
Oral: 400 to 800 mg combined hydroxides per tablet, capsule, or 5 mL suspension
H2 Histamine Receptor Blockers
Cimetidine (generic, Tagamet, Tagamet HB*)
Oral: 100*, 200, 300, 400, 800 mg tablets; 300 mg/5 mL liquid
Parenteral: 300 mg/2 mL, 300 mg/50 mL for injection
Famotidine (generic, Pepcid, Pepcid AC*)
Oral: 10 mg tablets*, gelcaps*; 20, 40 mg tablets; powder to reconstitute for 40 mg/5 mL
suspension
Parenteral: 10 mg/mL for injection
Nizatidine (Axid, Axid AR*)
Oral: 75 mg tablets*; 150, 300 mg capsules
Ranitidine (generic, Zantac, Zantac 75*)
Oral: 75*, 150, 300 mg tablets; 150 mg effervescent tablets; 150, 300 mg capsules; 15 mg/mL syrup
Parenteral: 1.0, 25 mg/mL for injection
Selected Anticholinergic Drugs
Atropine (generic)
Oral: 0.4 mg tablets
Parenteral: 0.05, 0.1, 0.3, 0.4, 0.5, 0.8, 1 mg/mL for injection
Belladonna alkaloids tincture (generic)
Oral: 0.27–0.33 mg/mL liquid
Dicyclomine (generic, Bentyl, others)
Oral: 10, 20 mg capsules; 20 mg tablets; 10 mg/5 mL syrup
Parenteral: 10 mg/mL for injection
Glycopyrrolate (generic, Robinul)
Oral: 1, 2 mg tablets
Parenteral: 0.2 mg/mL for injection
l–Hyoscyamine (Anaspaz, others)
Oral: 0.125, 0.15 mg tablets; 0.375 mg timed-release capsules; 0.125 mg/5 mL oral elixir and
solution
Parenteral: 0.5 mg/mL for injection
Methscopolamine (Pamine)
Oral: 2.5 mg tablets
Propantheline (generic, Pro-Banthine)
Oral: 7.5, 15 mg tablets
Scopolamine (generic)
Oral: 0.4 mg tablets
Parenteral: 0.3, 0.4, 0.86, 1 mg/mL for injection
Tridihexethyl (Pathilon)
Oral: 25 mg tablets
Proton Pump Inhibitors
Esomeprazole (Nexium)
Oral: 20, 40 mg delayed-release capsules
Omeprazole (Prilosec)
Oral: 10, 20, 40 mg delayed-release capsules
Lansoprazole (Prevacid)
Oral: 15, 30 mg delayed-release capsules; 15, 30 mg enteric-coated granules for oral suspension
Pantoprazole (Protonix)
Oral: 20, 40 mg delayed release tablets
Parenteral: 40 mg/vial powder for IV injection
Rabeprazole (Aciphex)
Oral: 20 mg delayed-release tablets
Mucosal Protective Agents
Misoprostol (Cytotec)
Oral: 100,
Sucralfate (generic, Carafate)
Oral:
Digestive Enzymes
Pancrelipase (Cotazym, Pancrease, Viokase, others)
Oral: Capsules, tablets, or powder containing lipase, protease, and amylase activity. See
manufacturers‘ literature for details.
Drugs for Motility Disorders & Selected Antiemetics
Alosetron (Lotronex)
Oral: 1 mg tablets
Cisapride (Propulsid)
Available in the USA only from the manufacturer, 877-795-4247
Dolasetron (Anzemet)
Oral: 50, 100 mg tablets
Parenteral: 20 mg/mL for injection
Dronabinol (Marinol)
Oral: 2.5, 5, 10 mg capsules
Granisetron (Kytril)
Oral: 1 mg tablets
Parenteral: 1 mg/mL for injection
Metoclopramide (generic, Reglan, others)
Oral: 5, 10 mg tablets; 5 mg/5 mL syrup, 10 mg/mL concentrated solution
Parenteral: 5 mg/mL for injection
Ondansetron (Zofran)
Oral: 4, 8, 24 mg tablets; 4 mg/5 mL solution
Parenteral: 2 mg/mL for IV injection
Prochlorperazine (Compazine)
Oral: 5, 10, 25 mg tablets; 10, 15, 30 mg capsules; 1 mg/mL solution
Rectal: 2.5, 5, 25 mg suppositories
Parenteral: 5 mg/mL for injection
Tegaserod (Zelnorm)
Oral: 2, 6 mg tablets
Selected Anti-Inflammatory Drugs Used in Gastrointestinal Disease
Balsalazide (Colazal)
Oral: 750 mg capsules
Budesonide (Entocort)
Oral: 3 mg capsules
Hydrocortisone (Cortenema, Cortifoam)
Rectal: 100 mg/60 mL unit retention enema; 90 mg/applicatorful intrarectal foam
Mesalamine (5-ASA)
Oral: Asacol: 400 mg delayed-release tablets; Pentasa: 250 mg controlled-release capsules
Rectal: Rowasa: 4 g/60 mL suspension; 500 mg suppositories
Methylprednisolone (Medrol Enpack)
Rectal: 40 mg/bottle retention enema
Olsalazine (Dipentum)
Oral: 250 mg capsules
Sulfasalazine (generic, Azulfidine, others)
Oral: 500 mg tablets and enteric-coated tablets
Infliximab (Remicade)
Parenteral: 100 mg powder for injection
Selected Antidiarrheal Drugs
Bismuth subsalicylate* (Pepto-Bismol, others)
Oral: 262 mg caplets, chewable tablets; 130, 262, 524 mg/15 mL suspension
Difenoxin (Motofen)
Oral: 1 mg (with 0.025 mg atropine sulfate) tablets
Diphenoxylate (generic, Lomotil, others)
Oral: 2.5 mg (with 0.025 mg atropine sulfate) tablets and liquid
Kaolin/pectin* (generic, Kaopectate, others)
Oral (typical):
Loperamide* (generic, Imodium, others)
Oral: 2 mg tablets, capsules; 1 mg/5 mL liquid
Selected Laxative Drugs*
Bisacodyl (generic, Dulcolax, others)
Oral: 5 mg enteric-coated tablets
Rectal: 10 mg suppositories
Cascara sagrada (generic)
Oral: 325 mg tablets; 5 mL per dose fluid extract (approximately 18% alcohol)
Castor oil (generic, others)
Oral: liquid or liquid emulsion
Docusate (generic, Colace, others)
Oral: 50, 100, 250 mg capsules; 100 mg tablets; 20, 50, 60, 150 mg/15 mL syrup
Glycerin liquid (Fleet Babylax)
Rectal liquid: 4 mL per applicator
Glycerin suppository (generic, Sani-Supp)
Lactulose (Chronulac, Cephulac)
Oral: 10 g/15 mL syrup
Magnesium hydroxide [milk of magnesia, Epsom Salt] (generic)
Oral: 400, 800 mg/5 mL aqueous suspension
Methylcellulose
Oral: bulk powder
Mineral oil (generic, others)
Oral: liquid or emulsion
Polycarbophil (Equalactin, Mitrolan, FiberCon, Fiber-Lax)
Oral: 500, 625 mg tablets; 500 mg chewable tablets
Polyethylene glycol electrolyte solution (CoLyte, GoLYTELY, others)
Oral: Powder for oral solution, makes one gallon (approximately
Psyllium (generic, Serutan, Metamucil, others)
Oral: 3.3, 3.4, 3.5, 4.03,
Senna (Senokot, Ex Lax, others)
Oral: 8.6, 15, 17, 25 mg tablets; 8.8, 15 mg/mL liquid
Drugs That Dissolve Gallstones
Monoctanoin (Moctanin)
Parenteral: 120 mL bottle for bile duct perfusion
Ursodiol (Actigall)
Oral: 300 mg (Actigall) capsules
*Over-the-counter formulations.
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.
Gastric antrum
I. Drugs for Lowering Acid Concentration
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
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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.
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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 have largely replaced H2 antagonists in the treatment of peptic ulcer disease.
Nocturnal acid suppression affords effective ulcer healing in the majority of patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime for acute, uncomplicated ulcers, resulting in ulcer healing rates greater than 80–90% after 6–8 weeks of therapy. For patients with acute peptic ulcers caused by H pylori, H2 antagonists no longer play a significant therapeutic role. For the minority of patients in whom H pylori cannot be successfully eradicated, H2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose in order to prevent ulcer recurrence (eg, ranitidine 150 mg, famotidine 20 mg). For patients with ulcers caused by aspirin or other NSAIDs, H2 antagonists provide rapid ulcer healing so long as the NSAID is discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given to promote ulcer healing.
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
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 theirsymptoms. 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 antiinflammatory 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)
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.
The action of aldosterone is, however, associated with increased renal excretion of KCl. The enteral and renal K+ loss add up to a K+ depletion of the body, evidenced by a fall in serum K+ concentration (hypokalemia). This condition is accompanied by
a reduction in intestinal peristalsis (bowel atonia). The affected individual infers “constipation,” again partakes of the purgative, and the vicious circle is closed (2).
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 absorbedparaffin 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.
Preparations Available
Antacids
Aluminum hydroxide gel* (Amphojel, ALternaGEL, others)
Oral: 300, 500, 600 mg tablets; 400, 500 mg capsules; 320, 450, 675 mg/5 mL suspension
Calcium carbonate* (Tums, others)
Oral: 350, 420, 500, 600, 650, 750, 1000, 1250 mg chewable tablets; 1250 mg/5 mL suspension
Combination aluminum hydroxide and magnesium hydroxide preparations* (Maalox,
Mylanta, Gaviscon, Gelusil, others)
Oral: 400 to 800 mg combined hydroxides per tablet, capsule, or 5 mL suspension
H2 Histamine Receptor Blockers
Cimetidine (generic, Tagamet, Tagamet HB*)
Oral: 100*, 200, 300, 400, 800 mg tablets; 300 mg/5 mL liquid
Parenteral: 300 mg/2 mL, 300 mg/50 mL for injection
Famotidine (generic, Pepcid, Pepcid AC*)
Oral: 10 mg tablets*, gelcaps*; 20, 40 mg tablets; powder to reconstitute for 40 mg/5 mL
suspension
Parenteral: 10 mg/mL for injection
Nizatidine (Axid,
Oral: 75 mg tablets*; 150, 300 mg capsules
Ranitidine (generic, Zantac, Zantac 75*)
Oral: 75*, 150, 300 mg tablets; 150 mg effervescent tablets; 150, 300 mg capsules; 15 mg/mL syrup
Parenteral: 1.0, 25 mg/mL for injection
Selected Anticholinergic Drugs
Atropine (generic)
Oral: 0.4 mg tablets
Parenteral: 0.05, 0.1, 0.3, 0.4, 0.5, 0.8, 1 mg/mL for injection
Belladonna alkaloids tincture (generic)
Oral: 0.27–0.33 mg/mL liquid
Dicyclomine (generic, Bentyl, others)
Oral: 10, 20 mg capsules; 20 mg tablets; 10 mg/5 mL syrup
Parenteral: 10 mg/mL for injection
Glycopyrrolate (generic, Robinul)
Oral: 1, 2 mg tablets
Parenteral: 0.2 mg/mL for injection
l–Hyoscyamine (Anaspaz, others)
Oral: 0.125, 0.15 mg tablets; 0.375 mg timed-release capsules; 0.125 mg/5 mL oral elixir and
solution
Parenteral: 0.5 mg/mL for injection
Methscopolamine (Pamine)
Oral: 2.5 mg tablets
Propantheline (generic, Pro-Banthine)
Oral: 7.5, 15 mg tablets
Scopolamine (generic)
Oral: 0.4 mg tablets
Parenteral: 0.3, 0.4, 0.86, 1 mg/mL for injection
Tridihexethyl (Pathilon)
Oral: 25 mg tablets
Proton Pump Inhibitors
Esomeprazole (Nexium)
Oral: 20, 40 mg delayed-release capsules
Omeprazole (Prilosec)
Oral: 10, 20, 40 mg delayed-release capsules
Lansoprazole (Prevacid)
Oral: 15, 30 mg delayed-release capsules; 15, 30 mg enteric-coated granules for oral suspension
Pantoprazole (Protonix)
Oral: 20, 40 mg delayed release tablets
Parenteral: 40 mg/vial powder for IV injection
Rabeprazole (Aciphex)
Oral: 20 mg delayed-release tablets
Mucosal Protective Agents
Misoprostol (Cytotec)
Oral: 100,
Sucralfate (generic, Carafate)
Oral:
Digestive Enzymes
Pancrelipase (Cotazym, Pancrease, Viokase, others)
Oral: Capsules, tablets, or powder containing lipase, protease, and amylase activity. See
manufacturers‘ literature for details.
Drugs for Motility Disorders & Selected Antiemetics
Alosetron (Lotronex)
Oral: 1 mg tablets
Cisapride (Propulsid)
Available in the
Dolasetron (Anzemet)
Oral: 50, 100 mg tablets
Parenteral: 20 mg/mL for injection
Dronabinol (Marinol)
Oral: 2.5, 5, 10 mg capsules
Granisetron (Kytril)
Oral: 1 mg tablets
Parenteral: 1 mg/mL for injection
Metoclopramide (generic, Reglan, others)
Oral: 5, 10 mg tablets; 5 mg/5 mL syrup, 10 mg/mL concentrated solution
Parenteral: 5 mg/mL for injection
Ondansetron (Zofran)
Oral: 4, 8, 24 mg tablets; 4 mg/5 mL solution
Parenteral: 2 mg/mL for IV injection
Prochlorperazine (Compazine)
Oral: 5, 10, 25 mg tablets; 10, 15, 30 mg capsules; 1 mg/mL solution
Rectal: 2.5, 5, 25 mg suppositories
Parenteral: 5 mg/mL for injection
Tegaserod (Zelnorm)
Oral: 2, 6 mg tablets
Selected Anti-Inflammatory Drugs Used in Gastrointestinal Disease
Balsalazide (Colazal)
Oral: 750 mg capsules
Budesonide (Entocort)
Oral: 3 mg capsules
Hydrocortisone (Cortenema, Cortifoam)
Rectal: 100 mg/60 mL unit retention enema; 90 mg/applicatorful intrarectal foam
Mesalamine (5-ASA)
Oral: Asacol: 400 mg delayed-release tablets; Pentasa: 250 mg controlled-release capsules
Rectal: Rowasa: 4 g/60 mL suspension; 500 mg suppositories
Methylprednisolone (Medrol Enpack)
Rectal: 40 mg/bottle retention enema
Olsalazine (Dipentum)
Oral: 250 mg capsules
Sulfasalazine (generic, Azulfidine, others)
Oral: 500 mg tablets and enteric-coated tablets
Infliximab (Remicade)
Parenteral: 100 mg powder for injection
Selected Antidiarrheal Drugs
Bismuth subsalicylate* (Pepto-Bismol, others)
Oral: 262 mg caplets, chewable tablets; 130, 262, 524 mg/15 mL suspension
Difenoxin (Motofen)
Oral: 1 mg (with 0.025 mg atropine sulfate) tablets
Diphenoxylate (generic, Lomotil, others)
Oral: 2.5 mg (with 0.025 mg atropine sulfate) tablets and liquid
Kaolin/pectin* (generic, Kaopectate, others)
Oral (typical):
Loperamide* (generic, Imodium, others)
Oral: 2 mg tablets, capsules; 1 mg/5 mL liquid
Selected Laxative Drugs*
Bisacodyl (generic, Dulcolax, others)
Oral: 5 mg enteric-coated tablets
Rectal: 10 mg suppositories
Cascara sagrada (generic)
Oral: 325 mg tablets; 5 mL per dose fluid extract (approximately 18% alcohol)
Castor oil (generic, others)
Oral: liquid or liquid emulsion
Docusate (generic, Colace, others)
Oral: 50, 100, 250 mg capsules; 100 mg tablets; 20, 50, 60, 150 mg/15 mL syrup
Glycerin liquid (Fleet Babylax)
Rectal liquid: 4 mL per applicator
Glycerin suppository (generic, Sani-Supp)
Lactulose (Chronulac, Cephulac)
Oral: 10 g/15 mL syrup
Magnesium hydroxide [milk of magnesia, Epsom Salt] (generic)
Oral: 400, 800 mg/5 mL aqueous suspension
Methylcellulose
Oral: bulk powder
Mineral oil (generic, others)
Oral: liquid or emulsion
Polycarbophil (Equalactin, Mitrolan, FiberCon, Fiber-Lax)
Oral: 500, 625 mg tablets; 500 mg chewable tablets
Polyethylene glycol electrolyte solution (CoLyte, GoLYTELY, others)
Oral: Powder for oral solution, makes one gallon (approximately
Psyllium (generic, Serutan, Metamucil, others)
Oral: 3.3, 3.4, 3.5, 4.03,
Senna (Senokot, Ex Lax, others)
Oral: 8.6, 15, 17, 25 mg tablets; 8.8, 15 mg/mL liquid
Drugs That Dissolve Gallstones
Monoctanoin (Moctanin)
Parenteral: 120 mL bottle for bile duct perfusion
Ursodiol (Actigall)
Oral: 300 mg (Actigall) capsules
*Over-the-counter formulations.
1. http://www.youtube.com/watch?v=HA8iL7hs5YY&feature=fvw
2. http://www.youtube.com/watch?v=rsrOoIeGnjA&feature=related
3. http://www.youtube.com/watch?v=Q–n_Q0qKXzg&feature=channel
4. http://www.youtube.com/watch?v=cWhLXdopQYo&feature=related
5. http://www.youtube.com/watch?v=q3986Yfl5cU&feature=related
6. http://www.youtube.com/watch?v=Z7xKYNz9AS0&feature=related
7. http://www.youtube.com/watch?v=XxvRbxhqoZk&feature=related
8. http://www.youtube.com/watch?v=QtDgQjOGPJM&feature=related
9. http://www.youtube.com/watch?v=_EtTWXQ5BiA&feature=related
