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Pharmacology of antiulcer medications
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Pharmacology of antiulcer medications

Disclosures: Andrew H Soll, MD Nothing to disclose. Nimish B Vakil, MD, AGAF, FACP, FACG, FASGE Consultant/Advisory Boards: AstraZeneca [GERD (Esomeprazole)]; Baxter [Probiotics]. Other Financial Interest: Salix [GERD (web-based review article)]. Mark Feldman, MD, MACP, AGAF, FACG Nothing to disclose. Shilpa Grover, MD, MPH Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2015. | This topic last updated: May 11, 2013.

INTRODUCTION — The treatment of peptic ulcers has changed dramatically in the past two decades, mirroring the revolution in understanding of the etiologies of peptic ulcers. Principles of treatment include:

  • Antibiotic therapy is indicated for ulcer disease associated with Helicobacter pylori (H. pylori) infection.
  • Anti-secretory drugs (H2 receptor antagonists [H2RAs] and proton pump inhibitors [PPIs]) are the mainstays of treatment for ulcer healing.
  • Maintenance therapy, once a mainstay of treatment for peptic ulcer disease, is no longer indicated after successful eradication of H. pylori [1].
  • Antacids, bismuth, and protective agents (eg, sucralfate) were shown to heal peptic ulcers in an era before the role of H. pylori was recognized, and, in retrospect, studies were performed on largely H. pylori-positive peptic ulcer patients. The efficacy of these agents for nonsteroidal antiinflammatory drug (NSAID) ulcers or for non-NSAID, non-H. pylori ulcers has not been established, and, thus, they have no role in the current treatment of peptic ulcers. The only exception is the use of bismuth as part of antibiotic regimens to cure H. pylori infection.
  • Prostaglandin analogues (eg, misoprostol) are effective for preventing NSAID-induced ulcers, but they have no established role for healing ulcers.

The pharmacology of antiulcer drugs, excluding the antibiotics used to treat H. pylori, will be reviewed here. The treatment of H. pylori as well as an overview of the natural history and treatment of peptic ulcer disease are discussed elsewhere. (See "Treatment regimens for Helicobacter pylori" and "Peptic ulcer disease: Management".)

H2 RECEPTOR ANTAGONISTS — H2 receptor antagonists (H2RAs) inhibit acid secretion by blocking histamine H2 receptors on the parietal cell (figure 1). H2RAs (eg, cimetidine, ranitidine, famotidine, and nizatidine) are still used for treatment and maintenance therapy of peptic ulcer disease, treatment of gastroesophageal reflux disease, and management of dyspepsia. However, they achieve less acid suppression than proton pump inhibitors.

H2RAs have efficacy for inhibiting acid secretion, preventing NSAID-induced ulcers, and in healing peptic ulcers when used at appropriate doses [2]. However, proton pump inhibitors have been shown to have superior healing rates for both duodenal and gastric ulcers [3]. In patients with NSAID-induced ulcers who require continued NSAID therapy while receiving treatment for ulcer disease, proton pump inhibitors are also superior to H2RAs [4].

Side effects of H2RAs include rare, severe adverse events, such as renal and hepatic toxicity. However, H2RA remain useful in some patients because of their low cost and good safety profiles. In addition, less acid inhibition may be an advantage by avoiding the consequences of profound acid inhibition.

Absorption and distribution — H2RAs are well absorbed after oral dosing; peak serum concentrations occur within one to three hours. Absorption is reduced 10 to 20 percent by concomitant antacid administration, but not by food.

All four drugs cross the blood-brain and placental barriers and are excreted in breast milk [5]. The distribution of cimetidine in cerebrospinal fluid appears to be increased in liver failure, suggesting that these patients are at increased risk of experiencing central nervous system (CNS) side effects [5]. (See 'CNS symptoms' below.)

Hepatic and renal metabolism — All four drugs are eliminated by a combination of hepatic and renal metabolism [5]. The bioavailability of cimetidine, famotidine, and ranitidine is reduced 30 to 60 percent by first pass hepatic metabolism [5]. By contrast, nizatidine undergoes very little hepatic metabolism; its bioavailability following oral dosing is 100 percent. Similarly, the bioavailability with intravenous dosing of all H2RAs approaches 100 percent, suggesting that dose reductions are warranted with intravenous administration, depending upon the goals of treatment. The half-life of cimetidine is prolonged with liver failure, but dose reduction is probably only necessary if renal failure accompanies severe hepatic disease [5,6].

Renal clearance of all four drugs is generally greater than accounted for by glomerular filtration, reflecting the importance of renal tubular secretion [5]. Cimetidine and, to a much lesser degree, ranitidine compete with creatinine for renal tubular secretion, causing a slight elevation in serum creatinine. Nizatidine and famotidine have the greatest dependence upon renal clearance; their half-life is more prolonged with renal failure.

Dose adjustments for renal failure are advised [7]. The dose of all the H2RAs is generally reduced by 50 percent in patients with moderate to severe renal failure [5,8]. Reducing the dose appears to decrease adverse effects [7].

The quantities of the H2 antagonists removed by peritoneal and hemodialysis are small; replacement doses are not necessary. Clearance is decreased in neonates and also in the elderly, suggesting that the dose should be reduced in individuals over age 75 years, particularly cimetidine [5].

Adverse effects — H2RAs are remarkably safe drugs; in randomized trials, the frequency of adverse reactions is generally similar to placebo [9]. A number of uncommon side effects have been reported, primarily as isolated cases or in retrospective uncontrolled series. However, causality cannot be established from the temporal association between drug use and an untoward effect, particularly when the clinical situation is complicated by serious medical illness and the use of multiple drugs [10]. In addition, conclusions regarding causality can only be inferred with drug rechallenge, which is rarely performed. Thus, in the absence of controlled comparisons, only limited conclusions can be drawn regarding the relative occurrence of uncommon side effects with the H2RAs.

Gynecomastia and impotence — Gynecomastia and impotence occur with cimetidine in a dose- and time-dependent fashion. Gynecomastia is rarely seen if treatment is limited to normal doses for eight weeks or less and, in one report, occurred in only 0.2 percent of men treated for 26 weeks [11]. In another study, gynecomastia or impotence were noted in one-half of men with hypersecretory disorders taking prolonged, high-dose cimetidine therapy; these problems gradually resolved when ranitidine was used in place of cimetidine [12]. Rare reports with other H2RA suggest that this effect is relatively specific for cimetidine.

Immune and hematopoietic effects — H2RAs have been implicated in idiosyncratic cases of myelosuppression, thrombocytopenia, neutropenia, anemia, and pancytopenia [13-16]. Hemolytic anemia also has been reported, although no anti-drug antibodies or hemolysis upon rechallenge has been found [17]. Concern persists that H2RAs may occasionally enhance transplant rejection and autoimmune or allergic diseases.

Other uncommon reactions may be mediated by immune mechanisms. These include polymyositis and interstitial nephritis with cimetidine [10,18], an immune complex rash with ranitidine, and fever with both cimetidine and ranitidine [13].

Some immunomodulatory effects may reflect a unique action of the imidazole ring of cimetidine rather than actions at H2 receptors [18]. Comparative data with other H2RAs are limited and conflicting.

Absorption of vitamin B12 depends upon gastric acid. As a result, it is not unexpected that long-term H2RA and proton pump inhibitor use has been associated with serum B12 deficiency [19]. Although more data are needed, the possibility of B12 deficiency should be kept in mind in any patient on chronic acid suppression.

CNS symptoms — H2RAs have been suspected to cause confusion, restlessness, somnolence, agitation, headaches, and dizziness and, with prolonged therapy, hallucinations, focal twitching, seizures, unresponsiveness, and apnea [10,20]. Although these symptoms are generally reversible upon discontinuation of the drug, cases with more persistent CNS symptoms have been reported [21].

Mental status changes appear to be most common in elderly patients in the intensive care unit who have comorbid renal or hepatic dysfunction [20]. Cimetidine has been implicated as the most frequent cause of these CNS symptoms, but similar side effects have also been described with ranitidine and famotidine [10,20]. CNS toxicity is rare during outpatient therapy. A study of H2RA effects on cognitive function among community dwelling elderly revealed a modest effect of borderline statistical significance [22]. Ranitidine also may cause headaches [17,20].

Hepatic dysfunction — Transient small increases in serum aminotransferases can occur with H2RAs, especially with high intravenous doses; these changes resolve during continued therapy. None of the four H2RAs is directly hepatotoxic; however, rare idiosyncratic or apparent immune hypersensitivity hepatitis, characterized by rash, fever, and/or eosinophilia, can occur [6,23]. The acute hepatitis is rapidly reversible after withdrawal of the drug. The pathological picture has included cholestatic, hepatocellular, and mixed reactions [24]. Hepatotoxicity has recurred with rechallenge in a sufficient number of cases to firmly establish this rare, but important association [24].

Serial monitoring of liver chemistries is not justified since these events are uncommon and the causality is uncertain. Nevertheless, checking hepatic enzymes approximately five days into high dose intravenous therapy is probably warranted. If hepatitis does develop in a patient receiving an H2RA, the drug should be immediately discontinued.

Cardiac effects — H2 receptors are present in the heart. Sinus bradycardia, hypotension, atrioventricular block, prolongation of the QT interval, and sinus and cardiac arrest have occurred with the rapid infusion of an H2RA [5,25,26]. Oral therapy also has been reported to cause cardiac toxicity, although clinically significant effects upon sinus rhythm or conduction are rare. Possible risk factors for cardiac events include rapid intravenous infusion, high dose, conditions that would delay drug clearance (eg, renal or hepatic dysfunction), and underlying cardiac disease [5].

Renal effects — Mild increases in serum creatinine have been observed with cimetidine. However, clinically significant renal disease appears to be limited to immune-mediated interstitial nephritis. A review published in 2001 [24] identified 25 published reports of acute interstitial nephritis with H2RA and an additional 16 cases in the Australian Adverse Drug Reaction Advisory Committee (ADRAC) database [24]. Renal biopsy and rechallenge have confirmed a sufficient number of cases to substantiate this rare association. Onset ranged from 1 day to 11 months after initiation of therapy. The clinical presentation was nonspecific, including sterile pyuria, proteinuria, leukocytosis, elevated erythrocyte sedimentation rate, and fatigue.

Drug interactions — Drug interactions have been described with some of the H2 receptor antagonists, particularly cimetidine. Thus, considering potential interactions is important when prescribing H2 receptor antagonists or adding medications to patients already taking them.

Teratogenicity — Although data remain limited, there is no evidence of major teratogenic effects with H2RAs [27].

PROTON PUMP INHIBITORS — The proton pump inhibitors (PPIs) (eg, omeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, and esomeprazole) effectively block acid secretion by irreversibly binding to and inhibiting the hydrogen-potassium ATPase pump that resides on the luminal surface of the parietal cell membrane (figure 1). There are three phases of their action:

  • They are weak bases that are concentrated in the acidic compartments of the parietal cell
  • Once there, the inactive prodrug is activated by the acid environment
  • A reactive sulfhydryl group then forms a disulfide bond with a cysteine residue on the H-K-ATPase pump, thereby inactivating the enzyme

Acidic compartments within the stimulated parietal cell are essential for activation of a PPI; in other words, the parietal cell has to be active in order to be inhibited by PPIs. Thus, PPIs work poorly in fasting patients or in those receiving simultaneous dosing with other antisecretory agents (H2 receptor antagonists, anticholinergic agents, misoprostol, or somatostatin). If the parietal cell is inhibited in the six hours following PPI dosing, PPI efficacy will be compromised. PPIs are most effective when taken 30 to 60 minutes before meals so that they are in the bloodstream in the few post-prandial hours when parietal cells are stimulated.

PPIs all achieve a similar level of acid secretory inhibition, although small differences in efficacy have been demonstrated when comparing various agents given in standard clinical doses. For example, esomeprazole was slightly more effective than other delayed release PPIs in healing of esophagitis. Slightly superior healing has also been demonstrated with immediate release omeprazole compared with lansoprazole or pantoprazole [28]. Twice daily dosing is recommended for large gastric ulcers but is not required for duodenal ulcers (see "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders"). Fixed dose combinations of the PPI esomeprazole with ibuprofen have been developed for use in the prevention of NSAID-induced gastroduodenal injury [29].

On the other hand, differences in healing rates with various PPIs observed in clinical trials of esophagitis have not been demonstrated in the treatment of peptic ulcer disease. As a result, our approach is based upon clinical experience and the pharmacology of these drugs. If a standard PPI therapy fails to heal an ulcer, we proceed with twice daily dosing, and if that treatment fails, we switch to another PPI. Esomeprazole or immediate-release omeprazole may be more effective than other PPIs. Immediate release omeprazole taken at bedtime also appears to be superior to delayed release PPIs taken before dinner [30]; this regimen may have some advantage for refractory ulcers. A complete discussion of the pharmacology, clinical efficacy, and safety of the PPIs is presented separately. (See "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders".)

COMPARATIVE EFFICACY OF ANTISECRETORY AGENTS — Proton pump inhibitors (PPIs) are more effective and long-lasting acid inhibitors than H2 receptor antagonists (H2RAs). As a result, they are superior in healing both gastric and duodenal ulcers, although the advantage for gastric ulcers is modest [31,32]. Although H2RAs are less potent inhibitors of gastric acid secretion with a longer duration of treatment, ulcer healing rates appear comparable to PPIs for uncomplicated ulcers. The clearest advantages for PPIs over H2RAs are as components of H. pylori antibiotic regimens and for treatment of hypersecretory states, such as gastrinoma and probably refractory ulcers.

Treatment needs to be adapted to the individual patient. H2RA-mediated acid inhibition is limited by tolerance, which is variable among subjects and likely contributes to poor efficacy. (See "Physiology of gastric acid secretion".) Tolerance does not occur for PPIs, but variable metabolism does account for some difference in efficacy. (See "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders".)

ANTACIDS — The ability of antacids containing aluminum and magnesium hydroxide to heal ulcers was established in an era when most ulcers were H. pylori-positive. The administered antacid buffering capacity poorly predicts ulcer healing, suggesting that healing is related not only to neutralization of gastric acid but also to other actions. In addition, in animal models, antacids protect the gastric mucosa against acute chemical injury independent of their effects on buffering acid.

The following are hypothesized mechanisms for the acid-independent actions of antacids [33,34]:

  • Aluminum hydroxide binds growth factors and enhances their binding to experimental ulcers, possibly serving to deliver growth factors to injured mucosa.
  • Antacids promote angiogenesis in injured mucosa [35].
  • Antacids bind bile acids and also inhibit peptic activity [36].
  • Heavy metals are well known to suppress, but generally not eradicate, H. pylori.

It is unclear which, if any, of these actions facilitate peptic ulcer healing.

Adverse effects — Antacid side effects depend upon the quantity consumed and the duration of therapy. Magnesium containing antacids cause diarrhea and hypermagnesemia; the latter only becomes important in patients with renal insufficiency. Antacids may also contain considerable sodium and volume overload can occur in susceptible patients.

Ingestion of large amounts of calcium and absorbable alkali, particularly calcium carbonate, can lead to hypercalcemia, alkalosis, and renal impairment, a constellation known as the milk-alkali syndrome [37]. (See "The milk-alkali syndrome".)

There are also potential adverse effects related to excessive aluminum absorption, which are discussed below. (See 'Aluminum toxicity' below.)

SUCRALFATE — Sucralfate (Carafate) is a sulfated polysaccharide, sucrose octasulfate, complexed with aluminum hydroxide. It prevents acute chemically-induced mucosal damage and heals chronic ulcers without altering gastric acid or pepsin secretion or significantly buffering acid [33,38]. Similar to aluminum-containing antacids, sucralfate stimulates angiogenesis and the formation of granulation tissue, possibly due to growth factor binding [33]. Sucralfate also binds to the injured tissue, thereby delivering growth factors and reducing access to pepsin and acid.

Aluminum hydroxide mediates some of the actions of sucralfate, but the sucrose octasulfate moiety may also have a role by contributing sulfhydryl groups to reduce oxidant damage to epithelial cells. The binding of this agent to the ulcer base is enhanced at a pH below 3.5, leading to the recommendation that the drug be administered 30 to 60 minutes before meals.

Sucralfate has been reported to suppress H. pylori and inhibit acid secretion in infected patients with duodenal ulcers [39]. No data are available to test the relevance of this action by comparing ulcer healing in patients with H. pylori-positive versus -negative duodenal ulcer.

Adverse effects — Sucralfate has minimal adverse effects other than possible aluminum toxicity [38]. It can bind other drugs if taken simultaneously, although the clinical consequences are minor.

Aluminum toxicity — Significant absorption of aluminum occurs with several antacid formulations and sucralfate [40]. Daily consumption of 120 mmol of aluminum-containing antacid tablets for four weeks increases serum and urinary aluminum levels [41]. A therapeutic dose of sucralfate contains about 0.8 g of aluminum and the aluminum absorption is comparable to that seen with antacids [42].

Aluminum is readily excreted by normal kidneys; urinary levels are elevated for one to three weeks after discontinuing therapy [43-45]. By comparison, significant aluminum retention occurs in patients with renal failure, and may result in neurotoxicity and anemia following treatment with either antacids or sucralfate [8,44,46]. As a result, calcium carbonate or acetate, rather than aluminum hydroxide is now the primary agent used to bind dietary phosphate. (See "Aluminum toxicity in chronic kidney disease" and "Treatment of hyperphosphatemia in chronic kidney disease".)

Simultaneous consumption of citrate enhances absorption of aluminum 50-fold in patients with normal renal function, resulting in considerable elevations in serum aluminum concentration [41,47]. To avoid enhanced aluminum absorption, especially in the setting of renal failure, it is advisable to avoid combining antacids and probably sucralfate with foods or other agents that contain citrate. If necessary to correct metabolic acidosis, alkali should be given as sodium bicarbonate, not sodium citrate.

The extent and consequences of aluminum deposition in tissues with sustained use of either class of agents have not been defined; the possibility of significant aluminum retention in the face of normal renal function is remote. Aluminum deposits have been reported in brain tissue in Alzheimer disease, but evidence points against significant aluminum deposition in the brain or a role for this metal in the pathogenesis of this disorder [48-50]. Nevertheless, more rigorous investigation of tissue aluminum is required in humans before firm conclusions can be reached.

Aluminum hydroxide blocks intestinal absorption of phosphate; two weeks of therapy with moderate doses can result in significant hypophosphatemia, especially if the patient is on a low phosphate diet or is phosphate-depleted for other reasons [51]. Sucralfate also binds phosphate leading to similar theoretical consequences; combining sucralfate and antacids can potentially amplify these effects [45]. (See "Causes of hypophosphatemia".)

BISMUTH — Several forms of bismuth were used for ulcer treatment long before the role of H. pylori was recognized. Colloidal bismuth subcitrate (CBS), also known as tripotassium dicitrato bismuthate and bismuth subsalicylate are used in treatment of H. pylori infection [52]. (See "Treatment regimens for Helicobacter pylori".)

The most dramatic action of these bismuth salts is the suppression of H. pylori [53]. Bismuth is not effective in H. pylori-negative ulcers, suggesting the healing efficacy of bismuth primarily reflects suppression of the infection. However, there are numerous studies from the pre-H. pylori era suggesting that bismuth also has other actions that may promote ulcer healing, including the following:

  • Inhibition of peptic activity but not pepsin secretion [54].
  • Bismuth from CBS may bind to ulcer craters [55,56].
  • Macrophages, recruited to the edge of the ulcer crater in CBS-treated rats, may promote healing [55].
  • CBS may increase mucosal prostaglandin production, and mucus and bicarbonate secretion.

Bismuth does not inhibit or neutralize gastric acid.

The subsalicylate salt of bismuth has received too little study to determine its antiulcer properties [53,57]. In the colon, bismuth salts react with hydrogen sulfide to form bismuth sulfide, which blackens the stools [53].

Adverse effects — The primary concern with bismuth compounds is bismuth intoxication; this was a problem primarily when bismuth subgallate was used for prolonged periods at high doses. Bismuth absorption varies with the specific form of bismuth; absorption is much greater with CBS than with BSS or bismuth subnitrate [58,59]. Coadministration of H2 receptor antagonists increases bismuth absorption from CBS, but not from BSS or bismuth subnitrate [60]. Nevertheless, significant clinical toxicity has not been reported in clinical trials with CBS or BSS [53,61]. Bismuth should be avoided or serum bismuth concentrations monitored in patients with renal failure [8].

The subsalicylate moiety in BSS is converted to salicylic acid and absorbed; however, salicylate in the absence of the acetyl group does not inhibit platelet function or appear to share the same high risk of aspirin for gastrointestinal bleeding [62-65]. However, the salicylate from bismuth subsalicylate will contribute to serum salicylate levels and cause salicylate toxicity, and combination with other salicylate products should therefore be avoided.

PROSTAGLANDINS — Prostaglandins, particularly of the E and I group, inhibit acid secretion by selectively reducing the ability of the parietal cell to generate cyclic AMP in response to histamine [66]. Prostaglandins also enhance mucosal defense mechanisms.

While several prostanoids have been tested for peptic ulcer healing, only misoprostol (Cytotec) has been approved for use in the United States, and not for ulcer healing but rather for prevention of nonsteroidal antiinflammatory drug (NSAID) induced gastric ulcer. Misoprostol is a 15-deoxy-15-hydroxy-16-methyl analogue of prostaglandin E1. Topical action appears critical for prostaglandin action; oral administration of misoprostol gives greater antisecretory efficacy and fewer side effects than systemic administration [67].

Adverse effects — The most frequent side effects of the E type prostanoids are dose-dependent crampy abdominal pain and diarrhea [68,69]. These side effects interfere with compliance in many patients. The problem of misoprostol-induced diarrhea has been addressed in several ways:

  • Educate the patient to anticipate and manage mild, usually transient cramps and diarrhea, but to stop the drug for more persistent or troublesome problems
  • The patient should be instructed not to use concomitant cathartic agents, to stop stool softeners unless absolutely necessary, and then to reevaluate the need for these agents after several weeks of therapy
  • The dose of misoprostol should begin at 100 micrograms three to four times daily, then increased to a maximal daily dose of 800 micrograms as tolerated

Lower doses of misoprostol have been used with some success for ulcer prevention with a lower incidence of side effects [70]. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Prostaglandins of the E group are uterotropic. Misoprostol has been given with or without mifepristone to induce abortion [68,71]. As a result, it is contraindicated in women of childbearing potential who are not on contraception. All patients should be informed of this risk to minimize the drug being inadvertently given by the patient to a pregnant woman.

SUMMARY AND RECOMMENDATIONS

  • The mainstay of ulcer treatment is curing Helicobacter pylori (H. pylori) and withdrawing nonsteroidal antiinflammatory drugs (NSAIDs).
  • Maintenance therapy may be required in patients with recurrent ulcer disease that is not related to H. pylori infection or to NSAID use and may be indicated if NSAID use is continued.
  • H2RAs inhibit acid secretion by blocking histamine H2 receptors on the parietal cell (figure 1). (See 'H2 receptor antagonists' above.)
  • The proton pump inhibitors effectively block acid secretion by irreversibly binding to and inhibiting the hydrogen-potassium ATPase pump that resides on the luminal surface of the parietal cell membrane (figure 1). (See 'Proton pump inhibitors' above.)
  • Although antacids and sucralfate induce ulcer healing, at present there is no clear role for their use in ulcer treatment. (See 'Sucralfate' above.)
  • Colloidal bismuth preparations also induce ulcer healing but their only role now for ulcer treatment is as part of antibiotic regimens for curing H. pylori. (See 'Bismuth' above.)
  • Several prostanoid analogues enhance peptic ulcer healing; only misoprostol has been approved for use in the United States for prevention, but not treatment, of NSAID-induced gastric ulcers. (See 'Prostaglandins' above.)

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