11 Pharm: Gastric Acidity, Peptic Ulcer Disease, GERD Meds Flashcards

1
Q

Clinical Case (p.3)

A
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2
Q

Rationale (p.18)

  • Normal or elevated gastric acid secretion in the setting of compromised innate mucosal protective mechanisms or barriers leads to/
  • The specific clinical manifestations include/
A
  • Normal or elevated gastric acid secretion in the setting of compromised innate mucosal protective mechanisms or barriers leads to mucosal injury, pain, hemorrhage, metaplasia, and/or even malignancy.
  • The specific clinical manifestations include
    • GERD (including erosive esophagitis and non-erosive reflux disease),
    • Barrett’s esophagus (Barrett’s metaplasia),
    • esophageal (peptic) strictures,
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3
Q

Background (p.4-5+10-16)

  • GERD
    • frequency
    • significantly impacts/
    • 7% of adults report/
    • 15% report/
  • Nexium (esomeprazole) and Prilosec (omeprazole)
A
  • GERD
    • the most symptomatic form of acid-related disorders,
    • significantly impacts one’s quality of life.
    • 7% of adults report daily heartburn,
    • 15% report having symptoms at least once monthly.
  • Nexium (esomeprazole) and Prilosec (omeprazole)
    • proton pump inhibitors,
    • among the top prescribed medications in the US.
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4
Q

Physiology of Gastric Acid Production (p.31-33)

  • Gastric acid secretion is controlled by multiple factors, each or which leads to/
  • What play important roles in the regultaion of acid secretion
  • Their respective specific receptors
    • receptors
    • localized to/
  • The H+, K+-ATPase (the proton pump) is activated via/
  • The H+, K+-ATPase consists of/
    • This pump generates/
A
  • Gastric acid secretion is controlled by multiple factors, each or which leads to the secretion of H+ by parietal cells located in the body and fundus of the stomach.
  • What play important roles in the regultaion of acid secretion
    • Neuronal factors (acetylcholine, ACh),
    • paracrine factors (histamine, H),
    • endocrine factors (gastrin, G)
  • Their respective specific receptors
    • M3, H2, CCK2 receptors
    • localized to the basolateral membrane of the parietal cell.
  • The H+, K+-ATPase (the proton pump) is activated via intra-cellular signaling pathways within the parietal cell
  • The H+, K+-ATPase consists of a large subunit and a smaller subunit
    • This pump generates the largest ion gradient known in vertebrates, with an intracellular pH of about 7.3 and an intracanalicular pH of about 0.8.
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5
Q

Physiology of Gastric Acid Production (p.31-33)

  • Efferent fibers of the vagus nerve synapse with/
  • ACh release from postganglionic vagal fibers
    • directly stimulate gastric acid secretion through/
    • indirectly affects the parietal cell through/
A
  • Efferent fibers of the vagus nerve synapse with ganglion cells of the enteric nervous system in the stomach.
  • ACh release from postganglionic vagal fibers
    • directly stimulate gastric acid secretion through a specific muscarinic (M) cholinergic receptor subtype, M3, located on the basolateral membrane of the parietal cells.
    • indirectly affects the parietal cell through
      • the stimulation of histamine release from the enterochromaffin-like (ECL) cells in the fundus (proximal stomach)
      • the stimulation of gastrin release from the G cells in the gastric antrum (distal stomach).
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6
Q

Physiology of Gastric Acid Production

  • Histamine
    • released from/
    • a critical regulator of/
      • ECL cells usually are found/
    • activates/
    • diffuses/
      • The ECL cells are the sole source of/
  • Gastrin
    • primarily present in/
    • stimulates/
    • has a less-important, direct effect on/
  • Somatostatin
    • localized in/
    • may inhibit/
    • a decrease in D cells in patients with H. pylori infection may lead to/
A
  • Histamine
    • released from ECL cells
    • a critical regulator of acid production through the H2 subtype of receptor.
      • ECL cells usually are found in close proximity to parietal cells.
    • activates the parietal cell in a paracrine fashion;
    • diffuses from its release site to the parietal cell.
      • The ECL cells are the sole source of gastric histamine involved in acid secretion.
  • Gastrin
    • primarily present in the antral G cells,
    • stimulates acid secretion in an indirect manner by causing the release of histamine from ECL cells;
    • has a less-important, direct effect on parietal cells
  • Somatostatin
    • localized in the antral D cells,
    • may inhibit gastrin secretion in a paracrine matter,
    • a decrease in D cells in patients with H. pylori infection may lead to excess gastrin production due to a reduced inhibition by somatostatin.
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7
Q

Innate Gastric Protective Mechanisms

  • The stomach is protected from acid damage by the following:
  • Prostaglandins E2 and I2
    • inhibit/
    • enhance/
A
  • The stomach is protected from acid damage by the following:
    • the presence of intercellular tight junctions between the gastric epithelial cells;
    • the presence of a mucin layer overlying the gastric epithelial cells;
    • the presence of prostaglandins in the gastric mucosa, and secretion of bicarbonate ions into the mucin layer.
  • Prostaglandins E2 and I2
    • inhibit gastric acid secretion by a direct effect on the parietal cell mediated by the EP3 receptor.
    • enhance mucosal blood flow and stimulate secretion of mucus and bicarbonate.
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8
Q

Agents Used for Suppression of Gastric Acid Production:
Proton Pump Inhibitors (p.37-38+41-42)

  • The most effective suppressors of gastric acid secretion
  • Current proton pump inhibitors (PPIs) on the market
  • PPIs
  • Mechanism of PPIs
  • PPIs have profound effects on/
  • Secretion of acid resumes only after/
A
  • 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
    • omeprazole (PRILOSEC, generic, OTC), esomeprazole (Nexium), lansoprazole (PREVACID), rabeprazole (ACIPHEX), pantoprazole (PROTONIX), and omeprazole/sodium bicarbonate (Zegerid)
  • PPIs
    • alpha-pyridylmethylsulfinyl benzimidazoles with different substitutions on the pyridine or the benzimidazole groups.
    • “pro-drugs,” requiring activation in an acid environment.
  • Mechanism of PPIs
    • These agents enter the parietal cells from the bloodstream 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 covalently 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.
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9
Q

Agents Used for Suppression of Gastric Acid Production:
Proton Pump Inhibitors (p.39)

  • PPIs are unstable at/
  • To facilitate their absorption and later activation in the parietal cell canaliculi, the oral dosage forms (“delayed release”) are supplied as/
  • The granules dissolve only at/
  • PPIs
    • absorption
    • highly/
    • metabolism
    • excretion
    • plasma half-life and duration of action
  • Chronic renal failure and liver cirrhosis do not appear to/
  • Hepatic disease reduces/
A
  • PPIs are unstable at a low pH (i.e. when exposed to acid in the gastric lumen in the absence of the appropriate substrate—the proton pump).
  • To facilitate their absorption and later activation in the parietal cell canaliculi, the oral dosage forms (“delayed release”) are supplied as
    • enteric-coated granules encapsulated in a gelatin shell (omeprazole and lansoprazole)
    • 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
    • rapidly absorbed,
    • highly protein-bound,
    • 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-life is about 1 to 2 hours, but duration of action is much longer by nature of their ability to covalently bind and deactivate proton pumps.
  • 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.
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10
Q

Agents Used for Suppression of Gastric Acid Production:
Proton Pump Inhibitors (p.44)

  • The requirement for acid to activate these drugs within the parietal cells has several important consequences.
  • PPIs inhibit the activity of/
  • side effects
A
  • The requirement for acid to activate these drugs within the parietal cells has several important consequences.
    • The drugs should be taken 30-60 minutes before a meal, since food will stimulate acid production by parietal cells;
    • co-administration of other acid-suppressing agents such as H2-receptor antagonists may diminish the efficacy of PPIs.
    • 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.
  • Side effects
    • 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.
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11
Q

Agents Used for Suppression of Gastric Acid Production:
Proton Pump Inhibitors

  • Chronic treatment with PPI’s/
    • Hypergastrinemia
    • Gastrin
  • teratogenic risk
  • chronic PPI use can lead to/
A
  • Chronic treatment with PPI’s decreases the absorption of vitamin B12
    • Hypergastrinemia (>500 ng/liter) occurs in approximately 5% to 10% of long-term PPI users.
    • Gastrin is a trophic factor for epithelial cells
      • elevations in gastrin can promote the growth of different kinds of tumors in the gastrointestinal tract.
  • PPI’s have not been associated with a major teratogenic risk when used during the first trimester of pregnancy;
  • chronic PPI use can lead to
    • osteoporosis, presumably from impaired calcium absorption,
    • increased risk of hip fractures,
    • increased risk of community-acquired pneumonias,
    • increased risk intestinal infections such as that related to C. difficile.
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12
Q

Agents Used for Suppression of Gastric Acid Production:
Histamine H2-Receptor Antagonists (p.46)

  • Four H2-receptor antagonists (H2RAs) are currently on the market
  • Their different chemical structures/
  • H2RAs inhibit acid production by/
  • The most prominent effects of H2RAs are on/
    • less profound but still significant is/
    • These agents thus are particularly effective in/
  • the most important determinant of duodenal ulcer healing is/
    • some patients with reflux esophagitis who are being treated with PPIs may continue to produce/
A
  • Four H2-receptor antagonists (H2RAs) are currently on the market
    • cimetidine (TAGAMET), ranitidine (ZANTAC), famotidine (PEPCID), and nizatidine (AXID).
  • Their different chemical structures
    • do not alter the drugs’ clinical efficacies
    • 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) acid production.
    • These agents thus are particularly effective in suppressing nocturnal acid secretion, which reflects mainly basal parietal cell activity.
  • the most important determinant of duodenal ulcer healing is the level of nocturnal acidity.
    • 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, however, tachyphylaxis likely occurs.
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13
Q

Agents Used for Suppression of Gastric Acid Production:
Histamine H2-Receptor Antagonists (p.48)

  • absorption
  • protein-bound
  • metabolism
  • excretion
  • availability
  • Therapeutic levels
A
  • 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
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14
Q

Agents Used for Suppression of Gastric Acid Production:
Histamine H2-Receptor Antagonists (p.49)

  • The overall incidence of adverse effects/
  • Side effects
    • usually
    • Less-common
    • Gynecomastia
    • thrombocytopenia
  • placenta, breast milk, and teratogenic risk
  • absorption and bioavailability
  • Drug interactions
    • Cimetidine
A
  • 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 rarely associated with thrombocytopenia.
  • placenta, breast milk, and teratogenic risk
    • H2-receptor antagonists cross the placenta and are excreted in breast milk.
    • No teratogenic risk has been associated with these agents.
  • 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.
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15
Q

Agents Used for Suppression of Gastric Acid Production:
Prostaglandin Analogs: Misoprostol (p.52)

  • Prostaglandins PGE2 and PGI2
    • ?
    • inhibit acid production by/
    • PGE also can prevent gastric injury by its cytoprotective effects, which include/
    • Since NSAIDs inhibit prostaglandin formation, the synthetic prostaglandins provide a rational approach to/
  • Misoprostol
    • ?
    • The degree of inhibition of gastric acid secretion by misoprostol is directly related to/
A
  • 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 adenylate cyclase and decreased levels of intracellular cyclic adenosine monophosphate (cAMP).
    • PGE also can prevent gastric injury by its cytoprotective effects, which include stimulation of mucin and bicarbonate secretion 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)
    • 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
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16
Q

Agents Used for Suppression of Gastric Acid Production:
Prostaglandin Analogs: Misoprostol:
Misoprostol (p.55)

  • absorption
  • metabolism
  • After a single dose, inhibition of acid production can be seen/
  • Food and antacids/
  • elimination half-life
  • The most frequently reported side effect
  • can cause clinical exacerbations in patients with/
  • can be used in cases of/
  • pregnancy
A
  • rapidly absorbed
  • undergoes extensive and rapid first-pass metabolism (de-esterification) 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.
  • The most frequently reported side effect is diarrhea, with or without abdominal pain and cramps, which can occur in up to 30% of patients.
    • Diarrhea, which appears to be a dose-dependent response, is seen about 2 weeks after initiating therapy and often resolves spontaneously within a week.
    • It can be severe in some patients, requiring discontinuation.
  • can cause clinical exacerbations in patients with inflammatory bowel disease and hence should be avoided in these patients.
  • can be used in cases of severe constipation.
  • contraindicated during pregnancy, since it can cause abortion by increasing uterine contractility.
    • Since the H2RA’s and PPIs are more effective, safer, and inexpensive, misoprostol is rarely used and mostly of historic significance.
17
Q

Agents Used for Suppression of Gastric Acid Production:
Sucralfate (p.57)

  • process that can be inhibited by sulfated polysaccharides
  • consists of/
  • In an acid environment (pH < 4), it undergoes/
  • additional cytoprotective effects
  • bile salts
  • role of sucralfate in the treatment of/
A
  • process that can be inhibited by sulfated polysaccharides
    • In the presence of acid-induced damage, pepsin-mediated hydrolysis of mucosal proteins contributes to mucosal erosion and ulcerations.
  • 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 for whom reflux of bile is thought to play a role in pathogenesis.
  • The role of sucralfate in the treatment of acid-peptic disease has diminished in recent years.
18
Q

Agents Used for Suppression of Gastric Acid Production:
​Sucralfate (p.57-58)

  • activated by/
  • recommended to be taken/
  • The most commonly reported side effect
  • Aluminum
  • Since sucralfate forms a viscous layer in the stomach, it may/
A
  • activated by acid,
  • recommended to 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 of sucralfate is constipation (2%).
  • Aluminum relaxes intestinal smooth muscle.
    • Small amounts of aluminum can be absorbed with the use of sucralfate, and special attention needs 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.
19
Q

Agents Used for Suppression of Gastric Acid Production:
Antacids (p.60-61)

  • Historically
  • NaHCO3
  • CaCO3
  • Combinations of Mg2+ and Al3+ hydroxides
  • Magaldrate
  • Simethicone
A
  • 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.
  • The very water-soluble NaHCO3 is rapidly cleared from the stomach and presents both an alkali and a sodium load.
  • CaCO3 can neutralize 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.
20
Q

Agents Used for Suppression of Gastric Acid Production:
Antacids (p.61)

  • The presence of food/
  • Alkalinization of the gastric contents/
  • Al3+
  • Thus, Al(OH)3 and Mg(OH)2 taken concurrently/
  • Because of its capacity to enhance secretion and to form insoluble compounds, CaCO3/
  • The release of CO2 from bicarbonate and carbonate-containing antacids can cause/
A
  • The presence of food 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.
21
Q

Agents Used for Suppression of Gastric Acid Production:
Antacids (p.62)

  • clearance from the empty stomach and absorption
  • Antacids that contain aluminum, calcium, or magnesium/
  • In persons with normal renal function, the modest accumulations of Al3+ and Mg2+/
    • with renal insufficiency, however, absorbed Al3+ can contribute to /
  • hypercalcemia
  • alkalosis
  • These disturbances of acid-base balance by antacids/
  • milk-alkali syndrome
A
  • 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 in normal patients, the hypercalcemia from as little as 3 to 4 g per day can be problematic in patients with uremia.
  • Absorption of unneutralized NaHCO3 causes 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.
22
Q

Agents Used for Suppression of Gastric Acid Production:
Antacids

  • By altering gastric and urinary pH, antacids may/
  • Al3+ and Mg2+ compounds also are notable for their propensity to/
  • altered rates of absorption
  • In general, it is prudent to avoid/
A
  • 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.
23
Q

Specific Acid-Peptic Disorders and Therapeutic Strategies:
Gastroesophageal Reflux Disease (p.20+64-65)

  • The goals of GERD therapy/
  • efficacy of PPIs vs. H2-RAs
  • with GERD, the therapeutic approach is best tailored to/
    • the optimal dose for each individual patient should be determined based upon/
    • when 24-hour pH monitoring is indicated
  • A popular approach to GERD therapy consists of/
  • Conversely, once symptoms are controlled over a period of time/
  • Patients should be treated with/
  • Lifestyle modifications/
A
  • The goals of GERD therapy are complete resolution of symptoms and healing of esophagitis
  • PPIs are definitively more effective than H2-RAs in achieving both of these goals.
    • 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.
  • with GERD, the therapeutic approach is best tailored to the level of severity in the individual patient.
    • the optimal dose for each individual patient should be determined based upon symptom control.
    • Only in patients with refractory symptoms is 24-hour pH monitoring indicated, usually to exclude GERD as a cause.
  • 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.
  • Conversely, once symptoms are controlled over a period of time, “step-down” therapy is recommended (i.e. stepping down from a PPI to an H2RA and from H2RAs to antacids).
  • Patients should be treated with the least aggressive acid-suppressive regimen that completely controls their symptoms.
  • Lifestyle modifications other than weight loss are relatively ineffective.
24
Q

Specific Acid-Peptic Disorders and Therapeutic Strategies:
Gastroesophageal Reflux Disease (p.20+65-66)

  • Although some patients with mild GERD symptoms may be managed by/
  • What may be needed in patients with severe symptoms or extraintestinal manifestations of GERD
  • nocturnal acid breakthrough/
  • With the development of more-sophisticated tools for measuring the chemical content of gastric reflux, the role of bile/
    • what concurrent trial may prove useful
A
  • 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 (cough, hoarseness, reactive airway disease), twice-daily dosing with a PPI may be needed.
  • 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.
  • With the development of more-sophisticated tools for measuring the chemical content of gastric reflux, the role of bile is now becoming more recognized, especially in those non- or partially-responsive to aggressive acid-suppressive therapy.
    • Here, a concurrent trial of sucralfate or cholestyramine (bile acid binder) may prove useful.
25
Q

Specific Acid-Peptic Disorders and Therapeutic Strategies:
Peptic Ulcer Disease (p.21+23)

  • The pathophysiology of peptic ulcer disease (PUD)
  • Patients with duodenal ulcers on average produce/
  • In gastric ulcer patients, even the lower levels of acid can produce/
  • Both H. pylori and exogenous agents such as NSAIDs/
  • Over 90% of ulcers are associated with NSAID use or H. pylori infection of the stomach.
    • This infection may lead to/
  • Topical injury by the luminal presence of the drug/
  • The effects of these drugs are instead mediated systemically, with the critical element being/
  • In non-bleeding PUD, PPIs promote/
  • In the setting of complicated PUD with acute upper gastrointestinal bleeding, the theoretical benefits of acid-suppressive agents in this setting include/
  • In addition, clot formation is enhanced and its dissolution retarded at/
    • improved outcome with/
A
  • The pathophysiology of peptic ulcer disease (PUD)
    • 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.
  • In 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 NSAIDs interact with these factors in complex ways, leading to ulcer formation.
  • Over 90% of ulcers are associated with NSAID use or 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, resulting in higher acid production as well as impaired duodenal bicarbonate production.
  • 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 non-bleeding PUD, PPIs promote more rapid relief of duodenal ulcer symptoms and more rapid healing than do H2RA.
  • 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.
    • improved outcome with the use of omeprazole in certain populations of patients with ulcer-related bleeding.
26
Q

Specific Acid-Peptic Disorders and Therapeutic Strategies:
Peptic Ulcer Disease (p.25-29+67)

  • H. pylori
    • organism
    • associated with/
  • Because of its critical role in the pathogenesis of peptic ulcers in the majority of cases, it has become standard care to/
  • Treatment of H. pylori infection requires/
  • A PPI significantly enhances the effectiveness of/
  • Antibiotic resistance/
    • Clarithromycin resistance/
    • metronidazole resistance/
A
  • H. pylori
    • a gram-negative rod,
    • associated with gastritis and subsequent development of gastric and duodenal ulcers, gastric adenocarcinoma and gastric B-cell lymphoma–mucosal associated lymphoid tissue (MALT) 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 requires a 1-2 week course of “triple therapy” (two antibiotics and an acid suppressing agent) or even “quadruple therapy”
    • Single antibiotic regimens are ineffective and lead to resistance.
  • A PPI 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 an important factor in the failure to eradicate H. pylori.
    • 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.
27
Q

Specific Acid-Peptic Disorders and Therapeutic Strategies:
NSAID-Related Ulcers (p.24+68-69)

  • Chronic NSAID users have a 2% to 4% risk of developing/
  • Ulcer healing despite continued NSAID use is possible with the use of/
  • PPIs are superior to H2RAs and misoprostol in promoting/
A
  • 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
  • PPIs are superior to H2RAs and misoprostol in promoting healing of active ulcers as well as in preventing recurrence (while on NSAIDs) of both gastric ulcers and duodenal ulcers
28
Q

Specific Acid-Peptic Disorders and Therapeutic Strategies:
Zollinger-Ellison Syndrome (p.22)

  • Patients with this syndrome develop/
    • This can lead to/
  • Proton pump inhibitors/
A
  • Patients with this syndrome develop gastrinomas, usually located in the duodenum or panreas 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 required at high dosages with the goal of therapy being to reduce acid secretion
29
Q

Summary

  • the most important lifestyle modifications for GERD
  • Longstanding GERD is a risk factor for/
  • Most gastroduodenal ulcers are caused by/
  • Step up-step down therapy is based on/
  • PPIs
  • Consider PPI use with NSAID/
  • Treat H. pylori to reduce the risk for/
A
  • Weight loss and change in eating habits are the most important lifestyle modifications for GERD
  • Longstanding GERD is a risk factor for Barrett’s esophagus and esophageal adenocarcinoma.
  • Most gastroduodenal ulcers are caused by NSAIDs or H. pylori.
  • Step up-step down therapy is based on symptom
  • PPIs are safe, but theoretical long-term effects exist
  • _Consider PPI use with NSAID_S in those at risk for PUD
  • Treat H. pylori to reduce the risk for recurrent PUD