Gastrointestinal agents –1.

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)

Diuretics (Furosemidum, Hydrochlortiazidum, Clopamidum, Acidum etacrynicum, spironolactonum, Triamterenum, Mannitum pro injectionibus, Urea pro injectionibus, herba Egusetum arvence, herba Ortosiphoni, Lespenephril). Uterine Stimulant and Relaxants (Diniprost, Diniproston, Ergometrini maleas, oxytocinum, Pituitrinum, Estron, Estradioli propionas, Proserinum, Olei Ricinum, Chininum, Tocopheroli acetas, Progesteroni acetas, Atropini sulfas, Partusistenuim (Fenoterol). Drugs used in gout and hyperuricemia (Allopurinolum, Etamidum, Urodanum, urolesanum)

 

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).

Video-1

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

Video-2

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 4 g per day can be problematic in patients with uremia. Absorption of neutralized NaHCO₃ will cause alkalosis. Neutralized antacids also may cause alkalosis by permitting the absorption of endogenous NaHCO₃ spared by the addition of exogenous neutralizing equivalents into the gastrointestinal tract. These disturbances of acid-base balance by antacids usually are transient and clinically insignificant in persons with normal renal function. In the past, when large doses of NaHCO₃ and/or CaCO₃ were commonly administered with milk or cream for the management of peptic ulcer, the milk-alkali syndrome occurred frequently. This syndrome results from large quantities of Ca²⁺ and absorbable alkali; effects consist of hypercalcemia, reduced secretion of parathyroid hormone, retention of phosphate, precipitation of Ca²⁺ salts in the kidney, and renal insufficiency. Therapeutic regimens emphasizing the use of dairy products seldom are employed in current practice.         By altering gastric and urinary pH, antacids may alter rates of dissolution and absorption, the bioavailability, and renal elimination of a number of drugs. Al³⁺ and Mg²⁺ compounds also are notable for their propensity to adsorb drugs and to form insoluble complexes that are not absorbed. Unless bioavailability also is affected, altered rates of absorption have little clinical significance when drugs are given chronically in multiple doses. In general, it is prudent to avoid concurrent administration of antacids and drugs intended for systemic absorption. Most interactions can be avoided by taking antacids 2 hours before or after ingestion of other drugs.

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.

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 813, in particular, is essential for inhibition of acid production, which is irreversible for that pump molecule. PPIs have profound effects on acid production. When given in a sufficient dose, the daily production of acid can be diminished by more than 95%.  Secretion of acid resumes only after new molecules of the pump are inserted into the luminal membrane.PPIs are unstable at a low pH. The oral dosage forms (“delayed release”) are supplied as enteric-coated granules encapsulated in a gelatin shell (omeprazole and lansoprazole) or as enteric-coated tablets (pantoprazole and rabeprazole). The granules dissolve only at an alkaline pH, thus preventing degradation of the drugs by acid in the esophagus and stomach. PPIs are rapidly absorbed, highly protein bound, and extensively metabolized in the liver by the cytochrome P450 system (particularly CYP2C19 and CYP3A4). Their sulfated metabolites are excreted in the urine or feces. Their plasma half-lives are about 1 to 2 hours, but their durations of action are much longer. Chronic renal failure and liver cirrhosis do not appear to lead to drug accumulation with once-a-day dosing of the drugs. Hepatic disease reduces the clearance of lansoprazole substantially, and dose reduction should be considered in patients with severe hepatic disease.  The requirement for acid to activate these drugs within the parietal cells has several important consequences. The drugs should be taken with or before a meal, since food will stimulate acid production by parietal cells; conversely, coadministration of other acid-suppressing agents such as H₂-receptor antagonists may diminish the efficacy of proton pump inhibitors. Since not all pumps or all parietal cells are functional at the same time, it takes several doses of the drugs to result in maximal suppression of acid secretion. With once-a-day dosing, steady-state inhibition, affecting about 70% of pumps, may take 2 to 5 days.  Since the binding of the drugs’ active metabolites to the pump is irreversible, inhibition of acid production will last for 24 to 48 hours or more, until new enzyme is synthesized. The duration of action of these drugs, therefore, is not directly related to their plasma half-lives.

PPIs inhibit the activity of some hepatic cytochrome P450 enzymes and therefore may decrease the clearance of benzodiazepines, warfarin, phenytoin, and many other drugs.  PPIs usually cause few adverse effects (<3%); nausea, abdominal pain, constipation, flatulence, and diarrhea are the most common side effects. Subacute myopathy, arthralgias, headaches, and skin rashes also have been reported. 

Chronic treatment with PPI’s decreases the absorption of vitamin B₁₂, but insufficient data exist to demonstrate whether or not this leads to a clinically relevant deficiency. Hypergastrinemia (>500 ng/liter) occurs in approximately 5% to 10% of long-term PPI users. Gastrin is a trophic factor for epithelial cells, and there is a theoretical concern that elevations in gastrin can promote the growth of different kinds of tumors in the gastrointestinal tract. In rats undergoing long-term administration of proton pump inhibitors, there has been development of enterochromaffin-like cell hyperplasia and gastric carcinoid tumors secondary to sustained hypergastrinemia; this has raised concerns about the possibility of similar complications in human beings. There are conflicting data on the risk and clinical implications of enterochromaffin-like cell hyperplasia in patients on long-term proton pump inhibitor therapy. These drugs now have a track record of more than 15 years of use worldwide, and no major new issues regarding safety have emerged.  PPI’s have not been associated with a major teratogenic risk when used during the first trimester of pregnancy; caution, however, is still warranted.

II. Protective Drugs Sucralfate (A) contains numerous aluminum hydroxide residues. However, it is not an antacid because it fails to lower the overall acidity of gastric juice. After oral intake, sucralfate molecules undergo cross-linking in gastric juice, forming a paste that adheres to mucosal defects and exposed deeper layers. Here sucralfate intercepts H+. Protected from acid, and also from pepsin, trypsin, and bile acids, the mucosal defect can heal more rapidly. Sucralfate is taken on an empty stomach (1 h before meals and at bedtime). It is well tolerated; however, released Al3+ ions can cause constipation.

In the presence of acid-induced damage, pepsin-mediated hydrolysis of mucosal proteins contributes to mucosal erosion and ulcerations. This process can be inhibited by sulfated polysaccharides. Sucralfate (CARAFATE) consists of the octasulfate of sucrose to which aluminum hydroxide has been added. In an acid environment (pH < 4), it undergoes extensive cross-linking and polymerization to produce a viscous, sticky gel that adheres strongly to epithelial cells and even more strongly to ulcer craters for as long as 6 hours after a single dose.  In addition to inhibition of hydrolysis of mucosal proteins by pepsin, sucralfate may have additional cytoprotective effects, including stimulation of local production of prostaglandin and epidermal growth factor. Sucralfate also binds bile salts, accounting for its use in some patients with esophagitis or gastritis in whom reflux of bile is thought by some to play a role in pathogenesis. The role of sucralfate in the treatment of acid-peptic disease clearly has diminished in recent years. It still may be useful in the prophylaxis of stress ulcers, where its use may be associated with a lower incidence of nosocomial pneumonia compared to acid-suppressing therapy with its tendency to promote gastric bacterial colonization. Since it is activated by acid, it is recommended that sucralfate be taken on an empty stomach one hour before meals rather than after; the use of antacids within 30 minutes of a dose of sucralfate should be avoided.

          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)-1 in the mucosa and a consequent reduction in cytoprotective prostaglandins, PGE₂ and PGI₂. In uncomplicated PUD, PPIs promote more rapid relief of duodenal ulcer symptoms and more rapid healing than do H₂RA, although both classes of drugs are very effective in this setting.  In the setting of complicated PUD with acute upper gastrointestinal bleeding, the theoretical benefits of acid-suppressive agents in this setting include acceleration of healing of the underlying ulcer. In addition, clot formation is enhanced and its dissolution retarded at a higher pH.  Isolated studies suggest an improved outcome with the use of omeprazole in certain populations of patients with ulcer-related bleeding. Despite such studies and the results of meta-analysis, the benefits from empiric acid-suppressive therapy in patients with acute gastrointestinal bleeding remain somewhat controversial. Although PPIs are probably more effective than H₂RAs in this setting, the availability of intravenous preparations of H₂-receptor antagonists has led to their widespread use. This practice has since be replaced by intravenous proton pump inhibitors. H. pylori, a gram-negative rod, has been associated with gastritis and subsequent development of gastric and duodenal ulcers, gastric adenocarcinoma and gastric B-cell lymphoma. Because of its critical role in the pathogenesis of peptic ulcers in the majority of cases, it has become standard care to eradicate this infection in patients with gastric or duodenal ulcers. 

Such a strategy almost completely eliminates the risk of ulcer recurrence, provided patients are not taking NSAIDs. Eradication of H. pylori also is indicated in the treatment of MALT-lymphoma of the stomach, as this can regress significantly after such treatment. Treatment of H. pylori infection often requires a week course of “triple therapy”(two antibiotics and an acid suppressing agent). 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 between natural 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

Video-3

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).

Video-4

 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 (<15 mm), gallbladder  function is normal, liver disease is absent, and patients are of normal body weight. UCDA is more effective (daily dose, 8–10 mg) and better tolerated than is CDCA (15 mg/d; frequent diarrhea, elevation of liver enzymes in plasma). Stone formation may recur after cessation of successful therapy. Compared with surgical treatment, drug therapy plays a subordinate role. UCDA may also be useful in primary biliary cirrhosis.

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, 200 g tablets

Sucralfate (generic, Carafate)

Oral: 1 g tablets; 1 g/10 mL suspension

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): 5.85 g kaolin and 260 mg pectin per 30 mL suspension

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 4 L)

Psyllium (generic, Serutan, Metamucil, others)

Oral: 3.3, 3.4, 3.5, 4.03, 6 g psyllium granules or powder per packet

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.

Diuretics

The normal urinary system, male and female. (Source: Wynsbergke, D., Noback, C. & Carola, R. [1995]. Human anatomy & physiology [3rd ed., p. 889]. New York: McGraw-Hill.)

 

Drugs acting on the renal tubules are useful in ancuety of clinical conditions evolving abnormal eleclyte or water metabolism Because the anatomic gments of the nephron are highly specialized in function, the actions of each agent in this group can be bestiderstood in relation to its site of action in the nephron and the normal physiology of that segment.

Diuretics (saluretics) elicit increased production of urine (diuresis). In the strict sense,  the term is applied to drugs with a direct renal action. The predominant action of such agents is to augment urine excretion by inhibiting the reabsorption of NaCl and water.

The most important indications for diuretics are: Mobilization of edemas (A): In edema there is swelling of tissues due to accumulation of fluid, chiefly in the extracellular (interstitial) space. When a diuretic is given, increased renal excretion of Na+ and H2O causes a reduction in plasma volume with hemoconcentration. As a result, plasma  protein concentration rises along with oncotic pressure. 

As the latter operates to attract water, fluid will shift from interstitium into the capillary bed. The fluid content of tissues thus falls and the edemas recede. The decrease in plasma volume and interstitial volume means a diminution of the extracellular fluid volume (EFV).

Depending on the condition, use is made of: thiazides, loop diuretics, aldosterone antagonists, and osmotic diuretics. Antihypertensive therapy. Diuretics have long been used as drugs of first choice for lowering elevated blood pressure. Even at low dosage, they decrease peripheral resistance (without significantly reducing EFV) and thereby normalize blood pressure. Therapy of congestive heart failure. By lowering peripheral resistance, diuretics aid the heart in ejecting blood (reduction in afterload); cardiac output and exercise tolerance are increased. Due to the increased excretion of fluid, EFV and venous return decrease (reduction in preload). Symptoms of venous congestion, such as ankle edema and hepatic enlargement, subside. The drugs principally used are thiazides (possibly combined with K+-sparing diuretics) and loop diuretics. Prophylaxis of renal failure. In circulatory failure (shock), e.g., secondary to massive hemorrhage, renal production of urine may cease (anuria). By means of diuretics an attempt is made to maintain urinary flow. Use of either osmotic or loop diuretics is indicated.

Massive use of diuretics entails a hazard of adverse effects (A): (1) the decrease in blood volume can lead to hypotension and collapse; (2) blood viscosity rises due to the increase in erythro- and thrombocyte concentration, bringing an increased risk of intravascular coagulation or thrombosis.

When depletion of NaCl and water (EFV reduction) occurs as a result of diuretic therapy, the body can initiate counter-regulatory responses (B), namely, activation of the renin-angiotensin- aldosterone system. Because of the diminished blood volume, renal blood flow is jeopardized. This leads to release from the kidneys of the hormone, renin, which enzymatically catalyzes the formation of angiotensin I. Angiotensin I is converted to angiotensin II by the action of angiotensin-converting enzyme (ACE). Angiotensin II stimulates release of aldosterone. The mineralocorticoid promotes renal reabsorption of NaCl and water and thus counteracts the effect of diuretics. ACE inhibitors augment the effectiveness of diuretics by preventing this counter-regulatory response.

NaCl Reabsorption in the Kidney (A)

The smallest functional unit of the kidney is the nephron. In the glomerular capillary loops, ultrafiltration of plasma fluid into Bowman’s capsule (BC) yields primary urine. In the proximal tubules (pT), approx. 70% of the ultrafiltrate is retrieved by isoosmotic reabsorption of NaCl and water.

Diuretics

Thiazides and related diuretics inhibit the reabsorption The nephron is the functional unit of the kidney. Note the various tubules, the site of most diuretic activity. The loop of Henle is the site of action for the loop diuretics. Thiazide diuretics act at the ascending portion of the loop of Henle and the distal tube of the nephron.

In the thick portion of the ascending limb of Henle’s loop (HL), NaCl is absorbed unaccompanied by water. This is the prerequisite for the hairpin countercurrent mechanism that allows build-up of a very high NaCl  concentration in the renal medulla. In the distal tubules (dT), NaCl and water are again jointly reabsorbed.

At the end of the nephron, this process involves an aldosterone- controlled exchange of Na+ against K+ or H+. In the collecting tubule (C), vasopressin (antidiuretic hormone, ADH) increases the epithelial permeability for water, which is drawn into the hyperosmolar milieu of the renal medulla and thus retained in the body.

As a result, a concentrated urine enters the renal pelvis. Na+ transport through the tubular cells basically occurs in similar fashion in all segments of the nephron. The intracellular concentration of Na+ is significantly below that in primary urine. This concentration gradient is the driving force for entry of Na+ into the cytosol of tubular cells. A carrier mechanism moves Na+ across the membrane.

 Energy liberated during this influx can be utilized for the coupled outward transport of another particle against a gradient. From the cell interior, Na+ is moved with expenditure of energy (ATP hydrolysis) by Na+/K+-ATPase into the extracellular space. The enzyme molecules are confined to the basolateral parts of the cell membrane, facing the interstitium; Na+ can, therefore, not escape back into tubular fluid. All diuretics inhibit Na+ reabsorption. Basically, either the inward or the outward transport of Na+ can be affected. Osmotic Diuretics (B) Agents: mannitol, sorbitol. Site of action: mainly the proximal tubules. Mode of action: Since NaCl and H2O are reabsorbed together in the proximal tubules, Na+ concentration in the tubular fluid does not change despite the extensive  eabsorption of Na+ and H2O. Body cells lack transport mechanisms for polyhydric alcohols such as mannitol and sorbitol, which are thus prevented from penetrating cell membranes.  Therefore, they need to be given by intravenous infusion. They also cannot be reabsorbed from the tubular fluid after glomerular filtration. These agents bind water osmotically and retain it in the tubular lumen. When Na ions are taken up into the tubule cell, water cannot follow in the usual amount. The fall in urine Na+ concentration reduces Na+ reabsorption, in part because the reduced concentration gradient towards the interior of tubule cells means a reduced driving force for Na+ influx. The result of osmotic diuresis is a large volume of dilute urine. Indications: prophylaxis of renal hypovolemic failure, mobilization of brain edema, and acute glaucoma.

Diuretics of the Sulfonamide Type

These drugs contain the sulfonamide group -SO2NH2. They are suitable for oral administration. In addition to being filtered at the glomerulus, they are subject to tubular secretion. Their concentration in urine is higher than in blood. They act on the luminal membrane of the tubule cells. Loop diuretics have the highest efficacy. Thiazides are most frequently used. Their forerunners, the carbonic anhydrase inhibitors, are now restricted to special indications.

Carbonic anhydrase (CAH) inhibitors,  such as acetazolamide and sulthiame,act predominantly in the proximal tubules. CAH catalyzes CO2 hydration/ dehydration reactions: H+ + HCO3 –.H2CO3.H20 + CO2. The enzyme is used in tubule cells

to generate H+, which is secreted into the tubular fluid in exchange for Na+. There, H+ captures HCO3 –, leading to formation of CO2 via the unstable carbonic acid. Membrane-permeable CO2 is taken up into the tubule cell and used to regenerate H+ and HCO3 –. When the enzyme is inhibited, these reactions are slowed, so that less Na+, HCO3 – and water are reabsorbed from the fast-flowing tubular fluid. Loss of HCO3

– leads to acidosis. The diuretic effectiveness of CAH inhibitors decreases with prolonged use. CAH is also involved in the production of ocular aqueous humor. Present

indications for drugs in this class include: acute glaucoma, acute mountain sickness, and epilepsy. Dorzolamide can be applied topically to the eye to lower intraocular pressure in glaucoma.

Loop diuretics

 include furosemide (frusemide), piretanide, and bumetanide. With oral administration, a strong diuresis occurs within 1 h but persists for only about 4 h. The effect is rapid, intense, and brief (high-ceiling diuresis). The site of action of these agents is the thick portion of the ascending limb of Henle’s loop, where they inhibit Na+/K+/2Cl– cotransport. As a result, these electrolytes, together with water, are excreted in larger amounts. Excretion of Ca2+ and Mg2+ also increases.

Special toxic effects include: (reversible) hearing loss, enhanced sensitivity to renotoxic agents. Indications: pulmonary edema (added advantage of i.v. injection in left ventricular failure: immediate dilation of venous capacitance vessels _ preload reduction); refractoriness to thiazide diuretics, e.g., in renal hypovolemic failure with creatinine clearance reduction (<30 mL/min); prophylaxis of acute renal hypovolemic failure; hypercalcemia. Ethacrynic acid is classed in this group although it is not a sulfonamide.

 

 

Thiazide diuretics (benzothiadiazines) include hydrochlorothiazide, benzthiazide, trichlormethiazide, and cyclothiazide. A long-acting analogue is chlorthalidone. These drugs affect the  intermediate segment of the distal tubules, where they inhibit a Na+/Cl– cotransport. Thus, reabsorption of NaCl and water is inhibited. Renal excretion  of Ca2+ decreases, that of Mg2+ increases. Indications are hypertension, cardiac failure, and mobilization of edema. Unwanted effects of sulfonamidetype diuretics: (a) hypokalemia is a consequence of excessive K+ loss in the terminal segments of the distal tubules where increased amounts of Na+ are available for exchange with K+; (b) hyperglycemia and glycosuria; (c) hyperuricemia  —increase in serum urate levels may precipitate gout in predisposed patients. Sulfonamide diuretics compete with urate for the tubular organic anion secretory system. 

Pharmacokinetics. All of the thiazides are absorbed when given orally, but there are differences in their metabolism.  Chlorothiazide, the parent of the group, is less lipid- soluble and must be given m relatively large doses Chlorthalidone is slowly absorbed and therefore appears to have a longer duration of action. Indapamide is excreted primarily by the biliary system and is useful in patieiits_with renal insufficiency All of the thiazides are secreted by the organic acid secretory system and  compete to some extent with the secretion of unc acid by that system As a result, the uric acid secretory rate may be reduced, with a concomitant elevation in serum uric acid level. In the steady state, unc acid production and therefore renal excretion are not affected by the thiazides.

Pharmacodynamics. Thiazides inhibit NaCI reabsorption in the early segments of the distal tubule Early clearance  studies demonstrated an effect on NaCI reabsorption during excretion of diluted urine under water-loaded conditions . This finding suggested that the site of action was at a “cortical diluting segment,” since there was no renal excretion can theoretically be achieved by increasing urinary bicaibonate excretion with carbonic anhydrase inhibitors Similarly, renal excretion of weak acids (eg, aspirin) is increased by raising the urine pH. These effects are of relatively short  duration and require bicarbonate infusion to maintain continuing bicarbonate diuresis.

C. Reduction of Total Body Bicarbonate Stores: Carbonic anhydrase inhibition will cause acute sodium bicarbonate diuresis as long as the filtered load of bicarbonate exceeds the renal capacity for bicarbonate absorption This approach can be useful m chronic metabolic alkalosis associated with resistance to other diuretic agents Another example is  posthyperoapnic metabolic alkalosis. Carbonic anhydrase inhibitors can be used to correct this condition if saline administration is ineffective or contramdicated because of elevated cardiac filling pressures.

D. Acute Mountain Sickness: Weakness, breathlessness, dizziness, and nausea can occur m mountain climbers who rapidly ascend above 3000 m and overexert themselves. The symptoms are usually mild and last for a few days In some climbers, rapidly progressing pulmonary or cerebral edema can be life-threatening Acetazolamide increases performance status and decreases overall symptomatology A recent study (see Greene reference on p 188) proposed taking 500 mg (one sustained-release capsule) by mouth at night for 5 nights before a climb

E. Other Uses: Carbonic anhydrase inhibitors have been used as adjuvants for the treatment of epilepsy, in some forms of hypokaleimc periodic paralysis, and to increase urinary phosphate excretion during severe hyperphosphatemia. Toxicity A. Hyperchloremic Metabolic Acidosis: This is the predictable consequence of chronic reduction of body bicaibonate stores  Bicarbonate wasting will ultimately limit the diuretic efficacy of carbonic anhydrase inhibitors m direct proportion to the overall reduction in filtered load of bicarbonate.

B. Renal Stones: Phosphatuna and hypercalcluria occur during the bicarbonaturic response to carbonic anhydrase inhibition. Renal excretion of solubihzmg factors (eg, citrate) may decline with chronic use. Calcium salts are relatively insoluble at alkaline pH, which means that renal stone formation can occur. C. Renal K”^ Wasting: Potassium wasting can be severe, especially during the acute bicarbonate diuresis stage. This complication may limit the useful ness of carbonic anhydrase inhibitors in chronic metabolic alkalosis associated with prior diuretic ad-ministration

D. Other Toxicities: Drowsmess and pares thesias are common following large doses Hypersen- sitivity reactions (fever, rashes, bone marrow suppression, interstitial nephritis) can also occur

Potassium-Sparing Diuretics (A)

These agents act in the distal portion of the distal tubule and the proximal part of the collecting ducts where Na+ is reabsorbed in exchange for K+ or H+.

Their diuretic effectiveness is relatively minor. In contrast to sulfonamide diuretics, there is no increase in K+ secretion; rather, there is a risk of hyperkalemia. These drugs are suitable for oral administration. a) Triamterene and amiloride, in addition to glomerular filtration, undergo secretion in the proximal tubule. They act on the luminal membrane of tubule cells. Both inhibit the entry of Na+, hence its exchange for K+ and H+. They are mostly used in combination with thiazide diuretics, e.g., hydrochlorothiazide, because the opposing effects on K+ excretion cancel each other, while the effects on secretion of NaCl complement each other. b) Aldosterone antagonists. The mineralocorticoid aldosterone promotes  the reabsorption of Na+ (Cl– and H2O follow) in exchange for K+. Its hormonal effect on protein synthesis leads to augmentation of the reabsorptive capacity of tubule cells. Spironolactone, as well as its metabolite canrenone, are antagonists at the aldosterone receptor and attenuate the effect of the hormone. The diuretic effect of spironolactone develops fully only with continuous administration for several days. Two possible explanations are: (1) the conversion of spironolactone into and accumulation of the more slowly eliminated metabolite canrenone; (2) an inhibition of aldosterone-stimulated protein synthesis would become noticeable only if existing proteins had become nonfunctional and needed to be replaced by de novo synthesis. A particular adverse effect results from interference with gonadal hormones, as evidenced by the development of gynecomastia (enlargement of male breast). Clinical uses include conditions of increased aldosterone secretion, e.g., liver cirrhosis with ascites.

Plant that have diuretic properties

  

Agents influence on miometrium

 

Classification

Drugs which influence on miometrium

 І Influence mostly on miometrium contraction

                   1. Increase contractions

                       Oxytocine         Dinoprost (prostaglandine F2α )

                       Pituitrine          Dinoproston (prostaglandine E2 )

                       Hyphotocine

                   2. Decrease contraction (tokolytic substances)

                       Fenoterol                   Sodium oxybutyrate

                       Salbutamol       Magnesium sulphate

 ІІ Increase mostly miometrium tone

                       Ergometrini maleas    Cotarnine chloride

                       Ergotamine hydrotartrate

                       Ergotal

ІІІ Decrease tone of uterus cervix

                       Atropine sulphate      Dinoprost   Dinoproston

Tocolytics

History: Premature labor (uterine contraction beginning before the 37th week of gestation) occurs in as many as 15% of all pregnancies in the western hemisphere.

Conservative treatment with bedrest, hydration, and sedation is not always successful, and pharmacologic agents are sometimes needed. Ethanol was once extensively used as a tocolytic agent. Ethanol infusions were given to provide serum concentrations slightly below legal intoxication, producing adverse reactions commonly associated with ethanol use. Ethanol crosses the placenta, and the fetus can also experience the effects and complications of ethanol. Terbutaline, approved in 1974, was the first beta2-agonist used for tocolysis, however, it is not currently recommeded for this indication. In 1980, ritodrine, a beta2-agonist, became the only FDA-approved agent for the treatment of premature labor. Other beta-agonists, such as albuterol, have also been used but have not gained the popular clinical acceptance of ritodrine.

Currently, ritodrine is the most widely accepted and used tocolytic. Other agents have been used and are being studied to prevent uterine contractions and premature labor. Magnesium sulfate, an alternative to the betamimetic agents, is a relatively safe and effective option. Magnesium sulfate is more commonly used in obstetrics to prevent seizures associated with preeclampsia. Hormonal agents, such as progesterone and prostaglandin synthetase inhibitors (e.g., indomethacin, naprorex, aspirin), have been used with limited success and significant adverse reactions. Calcium-channel blockers are being studied with variable results; nifedipine appears to have a potential role for this indication.  Mechanism of Action: Tocolytic agents decrease uterine contraction. This action can be accomplished through different mechanisms of action. The betamimetic agents include the commonly used agents ritodrine and terbutaline. Other betamimetic agents have been studied including isoxsuprine, albuterol, metaproterenol, nylidrin, and fenoterol. Betamimetics preferentially affect beta-receptors, and they have little effect on alpha-adrenergic receptors. The stimulatory effect on beta2-adrenergic receptors results in the inhibition of smooth muscle contraction including smooth muscle in the uterus. Betamimetics probably stimulate the activation of the enzyme adenyl cyclase, increasing production of cyclic adenosine monophosphate (cAMP). The increase in cAMP produces vasodilation and muscle relaxation in vascular and smooth muscle. Increased cAMP may lower intracellular calcium by enhancing the efflux of calcium from vascular smooth muscle cells and preventing calcium transmembrane influx. Cyclic AMP may inactivate myosin kinase, reducing phosphorylation of myosin, relaxing smooth muscle, and preventing

uterine contraction.

The mechanism of the less commonly used tocolytics affect calcium or hormonal balance. Magnesium sulfate’s mechanism of action as a tocolytic is unclear. It has been suggested that magnesium antagonizes calcium, interfering with actin-myosin interaction and decreasing uterine contraction. Other proposed mechanisms include magnesium blocking or decreasing nerve transmission, or altering acetylcholine release or sensitivity. Calcium-channel blockers (e.g., verapamil, nifedipine) inhibit calcium influx into uterine smooth muscle. Decreased intracellular calcium relaxes the myometrium.

Prostaglandin synthetase inhibitors, such as indomethacin, inhibit prostaglandins responsible for myometrial and cervical ripening. Fetal prostaglandin inhibition can cause premature closure of the ductus arteriosus and intrauterine pulmonary hypertension. Myometrial and cervical ripening are also dependent on low progesterone concentrations. Administering progesterones could have a tocolytic effect by increasing progesterone serum concentrations.

Distinguishing Features/Adverse Reactions: The betamimetic agents all have similar adverse reactions, although they may be more intense with isoxsuprine than with either ritodrine or terbutaline. All can cause sinus tachycardia, hypotension, and/or angina. These effects are dose-related and can often be controlled by altering the infusion rate of the agents. Hyperglycemia is also a potential adverse reaction of the beta-agonists. The other tocolytic agents described have less efficacy and potentially more serious adverse reactions than do the betamimetics.

Oxytocin:

Synthesis: Synthesized as a large precursor from which both the hormone and its spedfic neurophysin are cleaved (recall that a neurophysin is a carrier protein for a posterior pituitary hormone). Neurons that synthesize oxytocin are present in both the SON and PVN.

Stimuli for release: 1. Stimulation of the nipple initiates a neurogenic reflex which results in stimulation of oxytocin release. Oxytocin stimulates myoepithelial cells which surround the acini of the breast. This contraction causes milk to move into the nipple. In the absence of this process milk let down cannot be stimulated even in a full breast. 2. Labor-stimulates uterine contraction and is thought to be particu1arly important in maintaining uterine tone after parturition. Pharmacological uses: 1. Labor induction, pregnancy termination. If used injudidously may cause tetanic uterine contractions with uterine rupture. Has fluid retaining effects (ADH like).

 

Preparations Available

Acetazolamide(generic, Diamox)

Oral: 125, 250 mg tablets

Oral sustained-release: 500 mg capsules

Parenteral: 500 mg powder for injection

Amiloride(generic, Midamor, combination drugs)

Oral: 5 mg tablets

Bendroflumethiazide (Naturetin)

Oral: 5, 10 mg tablets

Benzthiazide (Exna, combination drugs)

Oral: 50 mg tablets

Brinzolamide(Azopt)

Ophthalmic: 1% suspension

Bumetanide(generic, Bumex)

Oral: 0.5, 1, 2 mg tablets

Parenteral: 0.5 mg/2 mL ampule for IV or IM injection

Chlorothiazide (generic, Diuril, others)

Oral: 250, 500 mg tablets; 250 mg/5 mL oral suspension

Parenteral: 500 mg for injection

Chlorthalidone(generic, Thalitone, combination drugs)

Oral: 15, 25, 50, 100 mg tablets

Demeclocycline(Declomycin)

Oral: 150 mg tablets and capsules; 300 mg tablets

Dichlorphenamide (Daranide)

Oral: 50 mg tablets

Dorzolamide(Trusopt)

Ophthalmic: 2% solution

Eplerenone (Inspra)

Oral: 25, 50, 100 mg tablets

Ethacrynic acid(Edecrin)

Oral: 25, 50 mg tablets

Parenteral: 50 mg IV injection

Furosemide(generic, Lasix, others)

Oral: 20, 40, 80 mg tablets; 8 mg/mL solutions

Parenteral: 10 mg/mL for IM or IV injection

Hydrochlorothiazide (generic, Microzide, Hydro-DIURIL, combination drugs)

Oral: 12.5 mg capsules; 25, 50, 100 mg tablets; 10 mg/mL solution

Hydroflumethiazide (generic, Diucardin)

Oral: 50 mg tablets

Indapamide(generic, Lozol)

Oral: 1.25, 2.5 mg tablets

Mannitol(generic, Osmitrol)

Parenteral: 5, 10, 15, 20, 25% for injection

Methazolamide (generic, Neptazane)

Oral: 25, 50 mg tablets

Methyclothiazide (generic, Aquatensen)

Oral: 2.5, 5 mg tablets

Metolazone (Mykrox, Zaroxolyn) (Note: Bio-

Availability of Mykrox is greater than that of Zaroxolyn.)

Oral: 0.5 (Mykrox); 2.5, 5, 10 mg (Zaroxolyn) tablets

Polythiazide (Renese)

Oral: 1, 2, 4 mg tablets

Quinethazone (Hydromox)

Oral: 50 mg tablets

Spironolactone(generic, Aldactone)

Oral: 25, 50, 100 mg tablets

Torsemide(Demadex)

Oral: 5, 10, 20, 100 mg tablets

Parenteral: 10 mg/mL for injection

Triamterene(Dyrenium)

Oral: 50, 100 mg capsules

Trichlormethiazide (generic, Diurese, others)

Oral: 2, 4 mg tablets

 

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=Z7xKYNz9AS0&feature=related

6.     http://www.youtube.com/watch?v=XxvRbxhqoZk&feature=related

8.     http://www.youtube.com/watch?v=QtDgQjOGPJM&feature=related

7.     http://www.youtube.com/watch?v=_EtTWXQ5BiA&feature=related

9.     http://www.youtube.com/watch?v=9A1_BberZ8w&NR=1