Pharmacotherapy for Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease PDF

SectionVI Gastrointestinal Pharmacology Chapter 53. Pharmacotherapy for Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease / 1073 Chapter 54. Gastrointestinal Motility and Water Flux, Emesis, and Biliary and Pancreatic Disease / 1085...

SectionVI Gastrointestinal Pharmacology Chapter 53. Pharmacotherapy for Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease / 1073 Chapter 54. Gastrointestinal Motility and Water Flux, Emesis, and Biliary and Pancreatic Disease / 1085 Chapter 55. Pharmacotherapy of Inflammatory Bowel Disease / 1111 https://ebooksmedicine.net/ This page intentionally left blank  53 Chapter PHYSIOLOGY OF GASTRIC SECRETION Parietal Cell H+,K+-ATPase Pharmacotherapy for Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease Keith A. Sharkey and Wallace K. MacNaughton Therapeutic Uses and Adverse Effects AGENTS THAT ENHANCE MUCOSAL DEFENSE Gastric Defenses Against Acid Misoprostol PROTON PUMP INHIBITORS Sucralfate Mechanism of Action and Pharmacology Antacids ADME Other Acid Suppressants and Cytoprotectants Therapeutic Uses and Adverse Effects THERAPEUTIC STRATEGIES FOR SPECIFIC ACID-PEPTIC H2 RECEPTOR ANTAGONISTS DISORDERS Mechanism of Action and Pharmacology Gastroesophageal Reflux Disease ADME Peptic Ulcer Disease Therapeutic Uses and Adverse Effects Treatment of Helicobacter pylori Infection Tolerance and Rebound With Acid-Suppressing Medications NSAID-Related Ulcers Stress-Related Ulcers POTASSIUM-COMPETITIVE ACID BLOCKERS Zollinger-Ellison Syndrome Mechanism of Action and Pharmacology Functional Dyspepsia ADME Functional Esophageal Disorders The stomach has a number of critical functions in the processes of diges- (M3, BB2, H2, and CCK2, respectively) are on the basolateral membrane tion: storage, digestion, and defense. The volume of the stomach is quite of parietal cells in the body and fundus of the stomach. Some of these small at rest, but the gastric musculature can undergo receptive relaxation receptors are also present on ECL cells, where they regulate the release of to accommodate a meal volume of 1 to 2 L. Food is broken down in the histamine. The H2 receptor is a G protein-coupled receptor (GPCR) that presence of acid by the grinding actions of the thick muscular coats of the activates the Gs–adenylyl cyclase–cyclic AMP–PKA pathway (see Chapters 3 stomach, and the contents then pass in a regulated manner into the duode- and 43). ACh and gastrin signal through GPCRs that couple to the Gq- num. Gastric acid not only serves to facilitate digestion, but it also provides PLC-IP3-Ca2+ pathway in parietal cells; GRP uses the same signaling path- an effective antimicrobial milieu that facilitates defense against pathogens. way to activate gastrin secretion from G cells. In parietal cells, the cyclic Gastric acid and pepsin in the stomach normally do not produce AMP and the Ca2+-dependent pathways activate H+,K+-ATPase (the pro- damage or symptoms of acid-peptic diseases because of intrinsic defense ton pump), which exchanges H+ and K+ across the parietal cell membrane. mechanisms. The stomach is protected by a number of factors, collectively This pump generates the largest ion gradient known in vertebrates, with referred to as “mucosal defense,” many of which are stimulated by the an intracellular pH of about 7.3 and an intracanalicular pH of about 0.8. local generation of prostaglandins (PGs) and nitric oxide (NO). If these The important structures for CNS stimulation of gastric acid secre- defenses are disrupted, a gastric or duodenal ulcer may form. The treat- tion are the dorsal motor nucleus of the vagus, the hypothalamus, and ment and prevention of acid-related disorders are accomplished by the nucleus of the solitary tract. Efferent fibers originating in the dorsal decreasing gastric acidity and enhancing mucosal defense. The appreci- motor nuclei descend to the stomach via the vagus nerve and synapse ation that an infectious agent, Helicobacter pylori, plays a key role in the with ganglion cells of the enteric nervous system (ENS). ACh release pathogenesis of acid-peptic diseases revolutionized approaches to pre- from postganglionic vagal fibers directly stimulates gastric acid secretion vention and therapy of these common disorders. through muscarinic M3 receptors on the basolateral membrane of parietal Barriers to the reflux of gastric contents into the esophagus comprise cells. The CNS predominantly modulates the activity of the ENS via ACh, the primary esophageal defense. If these protective barriers fail and reflux stimulating gastric acid secretion in response to the sight, smell, taste, or occurs, dyspepsia or erosive esophagitis may result. Therapies are directed anticipation of food (the “cephalic” phase of acid secretion). ACh also at decreasing gastric acidity, enhancing the tone of the lower esophageal indirectly affects parietal cells by increasing the release of histamine from sphincter, and stimulating esophageal motility (see Chapter 54). the ECL cells in the fundus of the stomach and of gastrin from G cells in the gastric antrum (Engevik et al., 2020). The ECL cells, the source of gastric histamine, are usually near parietal Physiology of Gastric Secretion cells. Histamine acts as a paracrine mediator, diffusing from its site of Gastric acid secretion is a complex and continuous process: Neuronal release to nearby parietal cells, where it activates H2 receptors to stimulate (acetylcholine [ACh], gastrin-releasing peptide [GRP]); paracrine (his- gastric acid secretion. tamine); and endocrine (gastrin) factors regulate the secretion of H+ by Gastrin, produced by antral G cells, is the most potent inducer of acid parietal cells (acid-secreting cells) (Figure 53–1). Their specific receptors secretion. Multiple pathways stimulate gastrin release, including CNS https://ebooksmedicine.net/  1074 Abbreviations the gastroesophageal junction—the lower esophageal sphincter in asso- ciation with the diaphragm and angle of His—which prevents reflux of acidic gastric contents into the esophagus. The stomach protects itself ACh: acetylcholine from acid damage by a number of mechanisms that require adequate cAMP: cyclic adenosine monophosphate (cyclic AMP) mucosal blood flow. One key defense is the secretion of a mucous layer CCK: cholecystokinin that helps to protect gastric epithelial cells by trapping secreted bicarbon- CNS: central nervous system ate at the cell surface. Gastric mucus is soluble when secreted but quickly CYP: cytochrome P450 forms an insoluble gel that coats the mucosal surface of the stomach, DU: duodenal ulcer slows ion diffusion, and prevents mucosal damage by macromolecules ECL: enterochromaffin-like cell such as pepsin. Mucus production is stimulated by PGs E2 and I2, which also directly inhibit gastric acid secretion by parietal cells. Thus, drugs ENS: enteric nervous system that inhibit PG formation (e.g., NSAIDs, ethanol) decrease mucus secre- GERD: gastroesophageal reflux disease tion and predispose to the development of acid-peptic disease. The prox- GI: gastrointestinal imal part of the duodenum is protected from gastric acid through the GPCR: G protein-coupled receptor production of bicarbonate, primarily from mucosal Brunner’s glands. GRP: gastrin-releasing peptide Figure 53–1 outlines the rationale and pharmacological basis for the GU: gastric ulcer therapy of acid-peptic disease. The PPIs are used most commonly, fol- HIST: histamine lowed by the histamine H2 receptor antagonists. IP3: inositol 1,4,5-trisphosphate NO: nitric oxide CHAPTER 53 PHARMACOTHERAPY FOR GASTRIC ACIDITY, PEPTIC ULCERS, AND GERD NSAID: nonsteroidal anti-inflammatory drug Proton Pump Inhibitors OTC: over the counter PG: prostaglandin The most potent suppressors of gastric acid secretion are inhibitors of PK: protein kinase the gastric H+,K+-ATPase or proton pump (Figure 53–2). These drugs PLC: phospholipase C diminish the daily production of acid (basal and stimulated) by 80% to PPI: proton pump inhibitor 95% (Shin and Sachs, 2008). SARS-CoV-2 (COVID-19): severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019) Mechanism of Action and Pharmacology SST: somatostatin Six PPIs are available for clinical use: omeprazole and its S-isomer, esome- prazole, lansoprazole and its R-enantiomer, dexlansoprazole, rabeprazole, and pantoprazole. All PPIs have equivalent efficacy at comparable doses. Proton pump inhibitors are prodrugs that require activation in an acid environment. After absorption into the systemic circulation, the pro- activation, local distention, and chemical components of the gastric con- drug diffuses into the parietal cells of the stomach and accumulates in tents. In addition to releasing ACh, some vagal fibers to the stomach also the acidic secretory canaliculi. Here, it is activated by proton-catalyzed release GRP (a 27–amino acid peptide); GRP activates the BB2 bombesin formation of a tetracyclic sulfenamide (see Figure 53–2), trapping the receptor on G cells, activating the Gq-PLC-IP3-Ca2+ pathway and causing drug so that it cannot diffuse back across the canalicular membrane. The secretion of gastrin. Gastrin stimulates acid secretion indirectly by induc- activated form then binds covalently with sulfhydryl groups of cysteines ing the release of histamine by ECL cells; a direct effect on parietal cells in the H+,K+-ATPase, irreversibly inactivating the pump molecule. Acid also plays a lesser role. secretion resumes only after new pump molecules are synthesized and Somatostatin, produced by antral D cells, inhibits gastric acid secre- inserted into the luminal membrane, providing a prolonged (up to 24- tion. Acidification of the gastric luminal pH to less than 3 stimulates to 48-h) suppression of acid secretion, despite the much shorter plasma somatostatin release, which in turn suppresses gastrin release in a t1/2 of about 0.5 to 3 h of the parent compounds. Because they block the negative-feedback loop. Somatostatin-producing cells are decreased in final step in acid production, the PPIs effectively suppress stimulated acid patients with H. pylori infection, and the consequent reduction of soma- production, regardless of the physiological stimulus, as well as basal acid tostatin’s inhibitory effect may contribute to excess gastrin production. production. The amount of H+,K+-ATPase increases after fasting; therefore, PPIs Parietal Cell H+,K+-ATPase should be given before the first meal of the day. In most individuals, once- H+,K+-ATPase is the enzyme responsible for secreting protons into the daily dosing is sufficient to achieve an effective level of acid inhibition, lumen of the gastric gland (Engevik et al., 2020). It is a heterodimeric and a second dose, which is occasionally necessary, can be administered protein composed of two subunits that are the products of two genes. The before an evening meal. Rebound acid hypersecretion occurs following ATP4A gene encodes the α subunit that contains the catalytic sites of prolonged treatment with PPIs, and clinical studies suggest that rebound the enzyme and forms the membrane pore, and the ATP4B gene encodes after ceasing treatment can provoke symptoms such as dyspepsia. the β subunit of the H+,K+-ATPase, which contains an N-terminal cyto- To prevent degradation of PPIs by acid in the gastric lumen and plasmic domain, a transmembrane domain, and a highly glycosylated improve oral bioavailability, oral dosage forms are supplied in different extracellular domain. Hydronium ions bind to three active sites present formulations: in the α subunit, and secretion involves a conformational change that allows the movement of protons. This movement is balanced by the Enteric-coated pellets within gelatin capsules (rabeprazole) transport of K+. The stoichiometry of transport is pH dependent, varying Delayed-release tablets (lansoprazole, pantoprazole, rabeprazole) between two H+ and two K+ per molecule of ATP to one of each under Delayed-release capsules (dexlansoprazole, esomeprazole, omeprazole, more acidic conditions. Inhibiting the H+,K+-ATPase (or proton pump) lansoprazole) is the mainstay of modern pharmacotherapy for acid-related disorders. Delayed-release oral suspension (esomeprazole, omeprazole, pantoprazole) The delayed-release and enteric-coated preparations dissolve only at Gastric Defenses Against Acid alkaline pH, which improves the oral bioavailability of these acid-labile The extremely high concentration of H+ in the gastric lumen requires drugs. Patients for whom the oral route of administration is not avail- robust defense mechanisms to protect the esophagus, stomach, and prox- able can be treated parenterally with esomeprazole sodium, omeprazole imal small intestine (Wallace, 2008). The primary esophageal defense is sodium, or pantoprazole.  1075 Muscarinic Gastrin Gastrin antagonists G cell 1 M3 K+ K+ BB2 ACh Cl– Cl– CCK2 H2 GRP antagonists CCK2 Ca2+-dependent pathway K+ HIST HIST H2 Potassium-competitive H+, K+ acid blockers cAMP-dependent ATPase M1 ECL cell pathway Proton pump inhibitors NSAIDs H+ Antacids ACh EPr3 Parietal cell Bismuth C20 fatty PGE2 Metronidazole acids Misoprostol H. pylori Tetracycline ENS Clarithromycin SECTION VI GASTROINTESTINAL PHARMACOLOGY N neuron Amoxicillin Muscarinic antagonists M1 EPr3 Mucus ACh Sucralfate Cyto- protection Carben- oxolone M1 2 Pirenzepine 3 ACh HCO3– Superficial epithelial cell Mucous layer Gastric lumen pH 7 pH 2 Figure 53–1 Pharmacologist’s view of gastric secretion and its regulation: the basis for therapy of acid-peptic disorders. Shown are the interactions among neural input and a variety of enteroendocrine cells: an ECL cell that secretes histamine, a ganglion cell of the ENS, a G cell that secretes gastrin, a parietal cell that secretes acid, and a superficial epithelial cell that secretes mucus and bicarbonate. Physiological pathways, shown in solid black, may be stimulatory (+) or inhibitory (−). 1 and 3 indicate possible inputs from postganglionic cholinergic fibers; 2 shows neural input from the vagus nerve. Physiological agonists and their respective mem- brane receptors include ACh and its muscarinic (M) and nicotinic (N) receptors; GRP and its receptor, the BB2 bombesin receptor; gastrin and its receptor, the CCK2; HIST and the H2 receptor; and PGE2 and the EP3 receptor. A red line with a T bar indicates sites of pharmacological antagonism. A light blue dashed arrow indicates a drug action that mimics or enhances a physiological pathway. Shown in red are drugs used to treat acid-peptic disorders. NSAIDs can induce ulcers via inhibition of cyclooxygenase. Not shown is a physiological pathway that reduces acid secretion: a D cell that secretes SST, which inhibits G-cell release of gastrin. ADME once-a-day dosing of the PPIs. Hepatic disease substantially reduces the clearance of esomeprazole and lansoprazole. Thus, in patients with severe Because an acidic pH in the parietal cell acid canaliculi is required for hepatic disease, dose reduction is recommended for esomeprazole and drug activation and food stimulates acid production, these drugs ideally lansoprazole. should be given about 30 min before meals. Concurrent administration of food may reduce somewhat the rate of absorption of PPIs, but this effect is not thought to be clinically significant. Once in the small bowel, PPIs are Therapeutic Uses and Adverse Effects rapidly absorbed, highly protein bound, and extensively metabolized by Prescription PPIs are primarily used to promote healing of gastric and hepatic CYPs, particularly CYP2C19 and CYP3A4. Asians and Oceanians duodenal ulcers and to treat gastroesophageal reflux disease (GERD), are more likely than Caucasians or Africans to have the CYP2C19 geno- including erosive esophagitis, which is either complicated or unrespon- type that correlates with reduced metabolism of PPIs (25%–30% Asians, sive to treatment with H2 receptor antagonists. They are also used in ~60% Oceanians vs. ~15% Caucasians or Africans), which may contrib- conjunction with antibiotics for the eradication of H. pylori. PPIs also ute to heightened efficacy or toxicity in this ethnic group (Lima et al., are the mainstay in the treatment of pathological hypersecretory con- 2021). For chronic use of first-generation PPIs (omeprazole, lansoprazole, ditions, including the Zollinger-Ellison syndrome. Lansoprazole, panto- and pantoprazole) after efficacy has been achieved, reduction in the dose prazole, and esomeprazole are approved for treatment and prevention of is recommended for those individuals with a CYP2C19 genotype that recurrence of NSAID-associated gastric ulcers in patients who continue predicts reduced function (Lima et al., 2021). NSAID use. It is not clear if PPIs affect the susceptibility to NSAID- Because not all pumps and all parietal cells are active simultaneously, induced damage and bleeding in the small and large intestine. All PPIs maximal suppression of acid secretion requires several doses of the PPIs. are approved for reducing the risk of duodenal ulcer recurrence associated For example, it may take 2 to 5 days of therapy with once-daily dosing to with H. pylori infections. Over-the-counter omeprazole, esomeprazole, achieve the about 70% inhibition of proton pumps that is seen at steady and lansoprazole are approved for the self-treatment of acid reflux. state. More frequent initial dosing (e.g., twice daily) will reduce the time Therapeutic applications of the PPIs are discussed further in the section to achieve full inhibition but has not been shown to improve patient out- Therapeutic Strategies for Specific Acid-Peptic Disorders. come. The resulting proton pump inhibition is irreversible; thus, acid The PPIs generally cause remarkably few adverse effects and have a secretion is suppressed for 24 to 48 h, or more, until new proton pumps strong safety record (Malfertheiner et al., 2017a; Reimer, 2013). The most are synthesized and incorporated into the luminal membrane of parie- common side effects are headache, nausea, abdominal pain, constipa- tal cells. Chronic renal failure does not lead to drug accumulation with tion, flatulence, and diarrhea. Subacute myopathy, arthralgias, interstitial https://ebooksmedicine.net/  1076 OCH3 H3C CH3 N N S O NH OCH3 OMEPRAZOLE H+ OCH3 CYCLIC SULFENAMIDE SULFENIC ACID H3C CH3 OCH3 OCH3 H3C CH3 H 3C CH3 + Enzyme SH N + + S Enzyme N N S N NH S S CHAPTER 53 PHARMACOTHERAPY FOR GASTRIC ACIDITY, PEPTIC ULCERS, AND GERD N N H2O N NH OH OCH3 OCH3 OCH3 ENZYME-INHIBITOR COMPLEX Figure 53–2 Activation of a PPI from its prodrug form. Omeprazole is converted to a sulfenamide in the acidic secretory canaliculi of the parietal cell. The sulfen- amide interacts covalently with sulfhydryl groups in the proton pump, thereby irreversibly inhibiting its activity. Lansoprazole, rabeprazole, and pantoprazole undergo analogous conversions. nephritis, pharyngitis, and skin rashes also have been reported. PPIs are polyposis, and atrophic gastritis. This hypergastrinemia may predispose metabolized by hepatic CYPs and therefore may interfere with the elim- to rebound hypersecretion of gastric acid on discontinuation of therapy ination of other drugs cleared by this route. PPIs have been observed and may promote the growth of GI tumors, although the risk appears to interact with warfarin (esomeprazole, lansoprazole, omeprazole, and very low (Malfertheiner et al., 2017a; Nehra et al., 2018). There have been rabeprazole); diazepam (esomeprazole and omeprazole); atazanavir or associations made between long-term PPI use and increased risk of small nelfinavir (esomeprazole, dexlansoprazole, lansoprazole, omeprazole, intestinal bacterial overgrowth, chronic kidney disease, and dementia. pantoprazole, and rabeprazole); and cyclosporine (omeprazole and rabe- These studies are not yet supported by well-controlled prospective tri- prazole). Among the PPIs, only omeprazole inhibits CYP2C19 (thereby als, and the evidence for these significant adverse effects remains limited decreasing the clearance of disulfiram, phenytoin, and other drugs) and (Freedberg et al., 2017; Malfertheiner et al., 2017a; Nehra et al., 2018). induces the expression of CYP1A2 (thereby increasing the clearance of Recently, a dose relationship between the use of PPIs and more severe imipramine, several antipsychotic drugs, tacrolimus, and theophylline). infection and secondary infections in patients with the SARS-CoV-2 There is some evidence that PPIs can inhibit conversion of clopido- (COVID-19) virus has been described (Almario et al., 2021; Pranata grel (at the level of CYP2C19) to the active anticoagulating form, but et al., 2021). This finding highlights the importance of gastric acid for this is controversial (Huang et al., 2012). Pantoprazole is less likely to gastrointestinal defense and that PPI use should be limited to the lowest result in this interaction; concurrent use of clopidogrel and PPIs (mainly effective doses and only when indicated clinically. pantoprazole) significantly reduces GI bleeding without increasing adverse cardiac events (see Chapter 36). Another drug interaction is between methotrexate and PPI therapy because PPIs can competitively H2 Receptor Antagonists inhibit methotrexate elimination and thereby increase methotrexate levels. The arrival of selective histamine H2 receptor antagonists was a landmark Chronic treatment with PPIs decreases the absorption of vitamin B12 in the treatment of acid-peptic disease. Before the availability of the H2 (cobalamin), but the clinical relevance of this effect is not completely receptor antagonists, the standard of care was simply acid neutralization clear. Determination of serum vitamin B12 levels might be considered in in the stomach lumen, generally with inadequate results. The long history long-term PPI users, especially those on high-dose PPIs and if they also of safety and efficacy with the H2 receptor antagonists led to their avail- have dietary restrictions that may limit vitamin B12 intake (see Chapter 45 ability without a prescription. Increasingly, however, PPIs are replacing for details of the importance of vitamin B12 to human health). Loss of the H2 receptor antagonists in clinical practice. gastric acidity also may affect the bioavailability of such drugs as ketoco- nazole, ampicillin esters, and iron salts. There is an association between CH2CH2NH2 PPI use and hypomagnesemia, with some guidelines recommending NH N monitoring of magnesium levels in patients receiving long-term PPI therapy, particularly those also using diuretics or those with malabsorp- HISTAMINE tion disorders (Malfertheiner et al., 2017a; Nehra et al., 2018). Chronic use of PPIs has been reported to be associated with an increased risk of bone fracture and with increased susceptibility to certain infections (e.g., hospital-acquired pneumonia, community-acquired Clostridium difficile, H3C CH2SCH2CH2N CNHCH3 spontaneous bacterial peritonitis in patients with ascites). Hypergastrine- HN C N HN mia is more frequent and more severe with PPIs than with H2 receptor antagonists and associated with this is ECL hyperplasia, fundic gland CIMETIDINE  excreted in breast milk. Although no major teratogenic risk has been 1077 TABLE 53–1 INTRAVENOUS DOSES OF H2 RECEPTOR associated with these agents, caution is warranted when they are used in ANTAGONISTS pregnancy. All agents that inhibit gastric acid secretion may alter the rate of CIMETIDINE RANITIDINE FAMOTIDINE absorption and subsequent bioavailability of the H2 receptor antago- Intermittent 300 mg every 50 mg every 20 mg every 12 h nists (see Antacids section). Drug interactions with H2 receptor antag- bolus 6–8 h 6–8 h onists occur mainly with cimetidine, and its use has decreased markedly. Continuous 37.5–100 mg/h 6.25–12.5 mg/h 1.7 mg/h Cimetidine inhibits CYPs (e.g., CYP1A2, CYP2C9, and CYP2D6) and infusion thereby can increase the levels of a variety of drugs that are substrates for these enzymes. Ranitidine also interacts with hepatic CYPs, but with an affinity of only 10% of that of cimetidine. Famotidine and nizatidine are Mechanism of Action and Pharmacology even safer in this regard. Slight increases in blood alcohol concentration The H2 receptor antagonists inhibit acid production by reversibly com- may result from concomitant use of H2 receptor antagonists and alcohol. peting with histamine for binding to H2 receptors on the basolateral membrane of parietal cells (Black, 1993). Four different H2 receptor antagonists, which differ mainly in their pharmacokinetics and propen- Tolerance and Rebound With Acid-Suppressing sity to cause drug interactions, were available in the U.S. until recently: Medications cimetidine, ranitidine, famotidine, and nizatidine. However, due to con- Tolerance to the acid-suppressing effects of H2 receptor antagonists tamination issues, some preparations of ranitidine and nizatidine have may develop within 3 days of starting treatment and may be resistant to been withdrawn from use. These drugs are less potent than PPIs but SECTION VI GASTROINTESTINAL PHARMACOLOGY increased doses of the medications (Sandevik et al., 1997). Diminished still suppress 24-h gastric acid secretion by about 70%. Suppression of sensitivity to these drugs may result from the effect of the secondary basal and nocturnal acid secretion is about 70%; because suppression of hypergastrinemia to stimulate histamine release from ECL cells. nocturnal acid secretion is important in the healing of duodenal ulcers, evening dosing of an H2 receptor antagonist is adequate therapy in most cases. There is little evidence for the use of H2 receptor antagonists for the Potassium-Competitive Acid Blockers treatment of bleeding ulcers, and they are no longer recommended for this purpose. All four H2 receptor antagonists are available as prescription While PPIs were a significant advancement in the treatment of acid and over-the-counter formulations for oral administration. Intravenous peptic diseases and GERD, there are many gastrointestinal conditions, and intramuscular preparations of cimetidine, ranitidine, and famotidine such as nonerosive reflex disease and erosive esophagitis, where there also are available for use in critically ill patients (Table 53–1). remains significant unmet clinical need for more effective therapies. Potassium-competitive acid blockers have been developed over the last 30 years and have been found to rapidly suppress acid secretion. Cur- ADME rently, this drug class is available only in Asia. Clinical trials of one The H2 receptor antagonists are rapidly absorbed after oral administra- potassium-competitive acid blocker, vonoprazan, are currently being tion, with peak serum concentrations within 1 to 3 h. Absorption may conducted in the U.S. and Europe. be enhanced by food or decreased by antacids, but these effects probably are unimportant clinically. Therapeutic levels are achieved rapidly after intravenous dosing and are maintained for 4 to 5 h (cimetidine), 6 to 8 h Mechanism of Action and Pharmacology (ranitidine), or 10 to 12 h (famotidine). The t1/2 values of these agents after There are currently three potassium-competitive acid blockers available oral administration in adults range from 1 to 3 h; cimetidine clearance is for clinical use, the pyrimidine derivative revaprazan, the benzimidazole faster in children, reducing its t1/2 by about 30%. Only a small fraction of derivative tegoprazan, and the pyrrole derivative vonoprazan (Figure 53–3). these drugs is protein bound. The kidneys excrete these drugs and their The potassium-competitive acid blockers are weak bases that bind metabolites by filtration and renal tubular secretion, and it is important competitively and reversibly to the potassium binding site of the H+/ to reduce drug doses in patients with decreased creatinine clearance. K+-ATPase following protonation (Engevik et al., 2020). The large size Neither hemodialysis nor peritoneal dialysis clears significant amounts of these molecules prevents the access of K+ cations to their binding of these drugs. Hepatic metabolism accounts for a small fraction of clear- site, thus blocking activation of the H+/K+-ATPase. They accumulate to ance (from 4 pH > 5 ing nocturnal acid secretion remains to be established. Patients with Intragastric pH continuing symptoms on twice-daily PPIs are often treated by adding an H2 receptor antagonist at night. Although this can further suppress acid Figure 53–4 Comparative success of therapy with PPIs and H2 antagonists. production, the effect is short lived, probably due to the development of Data show the effects of a PPI (given once daily) and an H2 receptor antag- CHAPTER 53 PHARMACOTHERAPY FOR GASTRIC ACIDITY, PEPTIC ULCERS, AND GERD tolerance (Fackler et al., 2002). onist (given twice daily) in elevating gastric pH to the target ranges (i.e., pH 3 for duodenal ulcer, pH 4 for GERD, and pH 5 for antibiotic eradication of Therapy for Extraintestinal Manifestations of GERD H. pylori). Acid reflux has been implicated in a variety of atypical symptoms, includ- ing noncardiac chest pain, asthma, laryngitis, chronic cough, and other TABLE 53–2 ANTISECRETORY DRUG REGIMENS FOR TREATMENT OF GERD DRUG ADULT DOSAGE PEDIATRIC DOSAGE H2 receptor antagonists a Cimetidine 400 mg 4 times daily or 800 mg twice daily for 20–40 mg/kg/day divided every 6 h for 8–12 weeks 12 weeks Famotidine 10–20 mg twice daily for up to 12 weeks 0.5 mg/kg/day at bedtime or divided every 12 h (infants 12 years, 20 mg/day up to Esomeprazole sodium 20–40 mg daily (IV)e 8 weeks Esomeprazole strontium 24.65 or 49.3 mg daily for 4–8 weeks IVd,e: 0.5 mg/kg daily (infants >1 month); children: 10 mg daily (55 kg) Dexlansoprazole 30 mg daily for 4 weeks (nonerosive GERD); erosive 60 mg/day for 8 weeks then 30 mg/g for 6 months GERD: 60 mg daily up to 6 months, then 30 mg (erosive esophagitis) daily up to 6 months (maintenance therapy) 30 mg/day for 4 weeks (GERD) Lansoprazole 15 mg (nonerosive GERD) or 30 mg 15–30 mg dailyd for up to 12 weeks (erosive GERD) daily up to 8 weeks Omeprazole 20 mg daily 5–20 mg dailyd Pantoprazole 40 mg daily (erosive GERD) 20–40 mg dailyd for up to 8 weeks Rabeprazole 20 mg daily (erosive GERD) Children 1–11 years old: 5–10 mg daily up to 12 weeks >12 years: 20 mg daily up to 8 weeks Potassium competitive acid blockers Revaprazan 200 mg daily Tegoprazan 50 mg daily Vonoprazan 10–20 mg daily a Not for erosive disease. b For children and adolescents, individualize treatment duration and dose based on clinical response or pH determination (gastric or esophageal) and endoscopy. For infants, employ conservative measures (e.g., thickened feedings) and limit therapy to 8 weeks. c Indicates off-label use. d Varies by weight. e Used when oral PPI cannot be given; short-term use only. ear, nose, and throat conditions. PPIs (at higher doses) have been used Peptic Ulcer Disease 1081 with some success in certain patients with these disorders. Peptic ulcer disease is best viewed as an imbalance between mucosal GERD and Pregnancy defense factors (bicarbonate, mucin, PGs, NO, and other peptides and Acid reflux is estimated to occur in 30% to 50% of pregnancies, with an growth factors) and injurious factors (acid and pepsin) (Hunt et al., 2015; incidence approaching 80% in some populations (Richter, 2003). In the Wallace, 2008). On average, patients with duodenal ulcers produce more vast majority of cases, GERD ends soon after delivery and thus does not acid than do control subjects, particularly at night (basal secretion). represent an exacerbation of a preexisting condition. Because of its high Although patients with gastric ulcers have normal or even diminished prevalence and the fact that it can contribute to the nausea of pregnancy, acid production, ulcers rarely, if ever, occur in the complete absence of treatment often is required. Treatment choice in this setting is compli- acid. Presumably, weakened mucosal defense and reduced bicarbonate cated by the paucity of safety data about use during pregnancy for the production contribute to the injury from the relatively lower levels of most commonly used drugs. The FDA has ceased to use a lettered risk acid in these patients. H. pylori and exogenous agents such as NSAIDs classification system (A–D and X, progressing from no risk to high risk/ interact in complex ways to cause an ulcer. Up to 60% of peptic ulcers do not use in pregnancy), preferring a more flexible and descriptive are associated with H. pylori infection of the stomach. This infection system customized for each drug. In the old system, most drugs used may lead to impaired production of somatostatin by D cells and, in time, to treat GERD were considered safe for conservative use during preg- cause decreased inhibition of gastrin production, resulting in increased nancy (old category B), except for omeprazole (old category C), which acid production and reduced duodenal bicarbonate production. Table was to be used only when the benefits outweighed the risks. In the new 53–3 summarizes current recommendations for drug therapy of gas- system, physicians, pharmacists, and patients should consult the package troduodenal ulcers. insert for the most recent information on use in pregnancy. For cases of The PPIs relieve symptoms of duodenal ulcers and promote healing SECTION VI GASTROINTESTINAL PHARMACOLOGY GERD during pregnancy and breastfeeding, literature reviews (Ali and more rapidly than do H2 receptor antagonists, although both classes of Egan, 2007; Thélin and Richter, 2020) suggest a conservative progression drugs are effective in this setting (see Figure 53–4). A peptic ulcer rep- of treatments, starting with antacids, alginates, or sucralfate, agents that resents a chronic disease, and recurrence within 1 year is expected in are considered the first-line drugs in this setting. If symptoms persist, H2 most patients who do not receive prophylactic acid suppression. With receptor antagonists can be used, with cimetidine having the most estab- the appreciation that H. pylori plays a major etiopathogenic role in lished track record in this setting, and with nizatidine to be avoided due most peptic ulcers, prevention of relapse is focused on eliminating this to adverse data from animal studies. PPIs are reserved for women with organism from the stomach. Intravenous esomeprazole (80 mg IV over intractable symptoms or complicated reflux disease; considering available 30 min, followed by 8 mg/h continuous infusion for a total of 72 h, then data, lansoprazole and pantoprazole seem to be the safest choices. 40 mg orally or another single daily dose oral PPI, for an appropriate duration; off-label use) and pantoprazole (off-label use) are the pre- Pediatric GERD ferred therapy in patients with acute bleeding ulcers (Laine and Jensen, Reflux disease in infants and children is increasing at an alarming rate 2012; Wong and Sung, 2013). The theoretical benefit of maximal acid (Vandenplas, 2014). Children over 10 years can be diagnosed and treated suppression in this setting is to accelerate healing of the underlying ulcer. similarly to adults, but infants and very young children require careful In addition, a higher gastric pH enhances clot formation and retards clot diagnosis to rule out cow’s milk allergy or eosinophilic esophagitis. Many dissolution. nonpharmacologic approaches can be used to alleviate some of the very The NSAIDs also are frequently associated with peptic ulcers and troubling symptoms of this condition, which may not be due to acid reflux. bleeding. The effects of these drugs are mediated systemically; in the If acid reduction is indicated, PPIs are more effective than H2 receptor antag- stomach, NSAIDs suppress mucosal PG synthesis (particularly PGE2 onists; however, the therapeutic efficacy of PPIs in newborns and infants is and PGI2) and thereby reduce mucus production and cytoprotection (see low, and there is an increased risk of adverse effects, including respiratory Figure 53–1). Thus, minimizing NSAID use is an important adjunct to tract infections and gastroenteritis, which should be carefully considered. It gastroduodenal ulcer therapy. is likely PPIs are overused in the treatment of pediatric GERD. TABLE 53–3 REGIMENS FOR TREATING GASTRODUODENAL ULCERS IN ADULTSa DRUG ACTIVE ULCER MAINTENANCE THERAPY Proton pump inhibitors b Esomeprazole magnesium NSAID risk reduction: 20 or 40 mg daily for up to 6 months Esomeprazole strontium NSAID risk reduction: 24.65 or 49.3 mg daily for up to 6 months Lansoprazole 15 mg (DU) daily for 4 weeks 15 mg daily 15 mg (NSAID risk reduction) daily for up to 12 weeks 30 mg dailyc 30 mg (GU including NSAID associated) daily for up to 8 weeks Omeprazole 20 mg (DU and GU) daily for 4–8 weeks 20 mg dailyc Pantoprazole 20 mg (NSAID risk reduction) daily c 20 mg dailyc 20 mg (GU) dailyc Rabeprazole 20 mg (DU for up to 4 weeks; GUc) daily Prostaglandin analogue Misoprostol 200 μg four times daily (NSAID-associated ulcer prevention)d a There is little evidence for the use of H2 receptor antagonists for the treatment of bleeding ulcers. b Deslansoprazole is not labeled for the treatment of active ulcers. c Off-label use. d Only misoprostol 800 μg/day has been directly shown to reduce the risk of ulcer complications such as perforation, hemorrhage, or obstruction. (Rostom A, Moayyedi P, Hunt R. Canadian Association of Gastroenterology Consensus Group. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for https://ebooksmedicine.net/ gastroprotection: benefits versus risks. Aliment Pharmacol Ther, 2009, 29:481–496.)  1082 Treatment of Helicobacter pylori Infection NSAID-Related Ulcers Helicobacter pylori, a gram-negative rod, has been associated with gas- Chronic NSAID users have a 2% to 4% risk of developing a symptomatic tritis and the subsequent development of gastric and duodenal ulcers, ulcer, GI bleeding, or perforation. Ideally, NSAIDs should be discontin- gastric adenocarcinoma, and gastric B-cell lymphoma (Suerbaum and ued in patients with an ulcer if possible. Healing of ulcers despite con- Michetti, 2002). Because of the critical role of H. pylori in the pathogene- tinued NSAID use is possible with the use of acid-suppressant agents, sis of peptic ulcers, eradicating this infection is standard care in patients usually at higher doses and for a considerably longer duration than stan- with gastric or duodenal ulcers (Malfertheiner et al., 2013). Provided that dard regimens (e.g., ≥8 weeks). PPIs are superior to H2 receptor antag- patients are not taking NSAIDs, this strategy almost completely elimi- onists and misoprostol in promoting the healing of active ulcers and in nates the risk of ulcer recurrence. Eradication of H. pylori also is indi- preventing recurrence of gastric and duodenal ulcers in the setting of cated in the treatment of mucosa-associated lymphoid tissue lymphomas of continued NSAID administration (Rostom et al., 2009). The FDA has the stomach, which can regress significantly after such treatment. H. pylori approved fixed-dose combinations of NSAIDs with a PPI or H2 antag- eradication is also indicated for treatment of chronic atrophic gastritis and onist; these combinations are intended to lower the risk of ulcers in presence of intestinal metaplasia/dysplasia (with positive H. pylori biopsies). patients who regularly use NSAIDs for arthritic pain. Five important considerations influence the selection of an eradication regimen (Table 53–4) (Chey et al., 2017; Malfertheiner et al., 2017b): Stress-Related Ulcers Single-antibiotic regimens are ineffective in eradicating H. pylori Stress ulcers are ulcers of the stomach or duodenum that occur in the infection and lead to microbial resistance. Combination therapy with context of a profound illness or trauma requiring intensive care (Bardou two or three antibiotics (plus acid-suppressive therapy) is associated et al., 2015). The etiology of stress-related ulcers differs somewhat from with the highest rate of H. pylori eradication. that of other peptic ulcers, involving acid and mucosal ischemia. Because CHAPTER 53 PHARMACOTHERAPY FOR GASTRIC ACIDITY, PEPTIC ULCERS, AND GERD A PPI significantly enhances the effectiveness of H. pylori antibiotic of limitations on the oral administration of drugs in many patients with regimens containing amoxicillin and clarithromycin (see Figure 53–4). stress-related ulcers, intravenous H2 receptor antagonists have been used A regimen of 10 to 14 days of treatment appears to be better than extensively to reduce the incidence of GI hemorrhage due to stress ulcers. shorter treatment regimens. Now that intravenous preparations of PPIs are available, they are appro- Poor patient compliance is linked to the medication-related side effects priate to consider. However, there is some concern over the risk of pneu- experienced by as many as half of patients taking triple-agent regimens monia secondary to gastric colonization by bacteria in an alkaline milieu. and to the inconvenience of three- or four-drug regimens administered In this setting, sucralfate appears to provide reasonable prophylaxis several times per day. Packaging that combines the daily doses into one against bleeding without increasing the risk of aspiration pneumonia. convenient unit is available and may improve patient compliance. The emergence of resistance to clarithromycin and metronidazole Zollinger-Ellison Syndrome increasingly is recognized as an important factor in the failure to Patients with Zollinger-Ellison syndrome develop pancreatic or eradicate H. pylori. In the presence of in vitro evidence of resistance duodenal gastrinomas that stimulate the secretion of very large to metronidazole, amoxicillin should be used instead. In areas with amounts of acid, sometimes in the setting of multiple endo- a high frequency of resistance to clarithromycin and metronidazole, crine neoplasia, type I (Krampitz and Norton, 2013). This can a 14-day quadruple-drug regimen (three antibiotics combined with a lead to severe gastroduodenal ulceration and other consequences PPI) generally is effective therapy. of uncontrolled hyperchlorhydria. PPIs are the drugs of choice, usually given at about twice the routine dosage for peptic ulcers (omeprazole 60 mg daily, esomeprazole 80 mg daily, lansoprazole TABLE 53–4 THERAPY OF HELICOBACTER PYLORI 60 mg daily, rabeprazole 60 mg daily, or pantoprazole 120 mg daily); INFECTION some patients need two to three times these doses to control acid secre- tion. However, once control of acid secretion has been achieved, dose Triple therapy × 10–14 days: PPI + clarithromycin 500 mg + reduction is usually possible. PPIs are well tolerated and safe even at amoxicillin 1 g twice a day (metronidazole 500 mg twice a day can be very high doses. If PPIs are unable to control gastric acid secretion, the substituted for amoxicillin) long-acting somatostatin analogue octreotide (off-label indication) can Quadruple therapy × 10–14 days: PPI + metronidazole 250 mg + be given to inhibit secretion of gastrin. This is not a first-line agent due bismuth subsalicylate 300 mg + tetracycline 500 mg four times daily to unpredictable response rates and the side effects of the treatment. Or Sequential therapy: PPI + amoxicillin 1 g twice a day for 5 days Functional Dyspepsia followed by PPI + clarithromycin 500 mg and tinidazole/ The term functional dyspepsia refers to ulcer-like symptoms in patients metronidazole 500 mg twice a day for 5 days who lack overt gastroduodenal ulceration (Masuy et al., 2019). Func- tional dyspepsia can be subdivided into postprandial distress syndrome Or and epigastric pain syndrome, based on the presence of symptoms related PPI + amoxicillin 1 g twice a day + levofloxacin 250 or 500 mg twice a to meals. It is defined as the presence of one or more of the following: day for 10 days postprandial fullness, early satiation, epigastric pain or burning, and no PPI daily dosages: evidence of structural disease. It may be associated with gastritis (with Omeprazole: 20 mg twice a day (triple therapy); 40 mg daily or without H. pylori) or with NSAID use, but the pathogenesis of this (dual therapy) syndrome remains controversial. The PPIs appear to be moderately effective in the treatment of patients Lansoprazole: 30 mg twice a day (triple therapy); 30 mg three times with epigastric pain syndrome and are a first-line therapy (Masuy et al., daily for 14 days (dual therapy with amoxicillin) 2019). In general, twice-daily PPIs are no better than once-daily PPIs. The Rabeprazole: 20 mg twice a day for 7 days dosing is as for GERD (Table 53–2). H2 receptor antagonists are only mar- Pantoprazole: 40 mg twice a daya ginally effective for the treatment of functional dyspepsia. Because cen- tral mechanisms may contribute to functional dyspepsia either through Esomeprazole magnesium: 40 mg daily (triple therapy) visceral hypersensitivity or other mechanisms, tricyclic antidepressants Esomeprazole strontium: 49.3 mg daily (triple therapy) such as amitriptyline or desipramine (10–25 mg at night) (see Chapter Off-label use. a 18) can be considered in patients with functional dyspepsia whose symp- Data from Chey et al., 2017. toms persist despite PPI therapy for 8 weeks. Prokinetic agents such as metoclopramide (see Chapter 54) are a first-line therapy for the treatment disorders like achalasia, and GERD (Amarasinghe and Sifrim, 2014). 1083 of postprandial distress syndrome. The novel gastroprokinetic agent aco- There are four of these common disorders: (1) functional heartburn, (2) tiamide has been applied to postprandial distress syndrome with symp- functional chest pain, (3) functional dysphagia, and (4) globus. PPI ther- tom improvements noted in most trials (Masuy et al., 2019), and the apy (off-label use) as outlined previously is routinely used for the initial 5HT1A serotonin receptor agonist buspirone that relaxes the gastric fun- treatment of functional heartburn, functional chest pain, and globus. As dus (see Chapter 15) improved gastric accommodation and GI symptoms in functional dyspepsia, central mechanisms contribute to these disor- in patients with functional dyspepsia. Antacids are not generally helpful ders and similar approaches follow for the treatment of functional heart- for the treatment of functional dyspepsia. burn and functional chest pain if PPI therapy is ineffective, including the use of tricyclic antidepressants or selective serotonin reuptake inhibitors. Functional Esophageal Disorders For the treatment of globus, gabapentin or pregabalin is used. Functional esophageal disorders are disorders that cause esophageal symptoms and that are diagnosed based on negative results on stan- Acknowledgment: We are grateful to Dr. José Geraldo Ferraz for his critical dard esophageal tests, thereby excluding structural disorders, motility input to this chapter. Drug Facts for Your Personal Formulary: Antisecretory Agents and Gastroprotectives SECTION VI GASTROINTESTINAL PHARMACOLOGY Drugs Therapeutic Uses Clinical Pharmacology and Tips Proton Pump Inhibitors Dexlansoprazole Gastroesophageal reflux disease Generally well tolerated Erosive esophagitis Possible interaction with clopidogrel (controversial) Increased incidence of osteoporosis-related fractures of hip, wrist, or spine Diarrhea Interstitial nephritis May cause cyanocobalamin (vitamin B12) deficiency with daily long-term use (>3 years) Esomeprazole Gastric ulcers OTC forms for acid reflux Lansoprazole Duodenal ulcers Generally well tolerated Omeprazole Erosive esophagitis Possible interaction with clopidogrel (controversial) Pantoprazole Gastroesophageal reflux disease Increased incidence of osteoporosis-associated fractures of hip, wrist, or spine Helicobacter pylori eradication Diarrhea Zollinger-Ellison syndrome Interstitial nephritis May cause cyanocobalamin (vitamin B12) deficiency with daily long-term use (>3 years) Interactions with diagnostic investigations for neuroendocrine tumors Rabeprazole Gastroesophageal reflux disease Generally well tolerated Helicobacter pylori eradication Possible interaction with clopidogrel (controversial) Zollinger-Ellison syndrome Increased incidence of osteoporosis-associated bone fractures of hip, wrist, or spine Diarrhea Interstitial nephritis H2 Receptor Antagonists Cimetidine Gastric ulcer (to promote healing) No longer recommend for treating active ulcers Famotidine Duodenal ulcer (to promote healing) Generally well tolerated Nizatidine Gastroesophageal reflux disease Beware of drug interactions with cimetidine Ranitidine Potassium-Competitive Acid Blockers Revaprazan Gastric ulcer Generally well tolerated Tegoprazan Duodenal ulcer Only available in Asia Vonoprazan Gastroesophageal reflux disease Helicobacter pylori eradication (vonoprazan) Mucosal Defensive Agents Misoprostol Ulcer prophylaxis Rarely used because of side effects (especially ↑ uterine contractility) Not be used in women of childbearing potential or in pregnancy Diarrhea; exacerbation of inflammatory bowel disease Marketed in combination with diclofenac Sucralfate Initial treatment of GERD in pregnancy Generally well tolerated Constipation Antacids Acid reflux OTC; generally well tolerated; produce rapid but temporary effects Esophagitis Na+ and Al+3 loads: potential problems in cardiovascular and renal disease https://ebooksmedicine.net/  1084 Lima JJ, et al. 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